Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function.

PubMed

Perico, Luca; Morigi, Marina; Rota, Cinzia; Breno, Matteo; Mele, Caterina; Noris, Marina; Introna, Martino; Capelli, Chiara; Longaretti, Lorena; Rottoli, Daniela; Conti, Sara; Corna, Daniela; Remuzzi, Giuseppe; Benigni, Ariela

2017-10-17

Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, although cellular targets of such an effect are still ill-defined. Here, we show that human umbilical cord (UC)-MSCs transplanted into mice stimulate tubular cells to regain mitochondrial mass and function, associated with enhanced microtubule-rich projections that appear to mediate mitochondrial trafficking to create a reparative dialogue among adjacent tubular cells. Treatment with UC-MSCs in mice with cisplatin-induced acute kidney injury (AKI) regulates mitochondrial biogenesis in proximal tubuli by enhancing PGC1α expression, NAD + biosynthesis and Sirtuin 3 (SIRT3) activity, thus fostering antioxidant defenses and ATP production. The functional role of SIRT3 in tubular recovery is highlighted by data that in SIRT3-deficient mice with AKI, UC-MSC treatment fails to induce renoprotection. These data document a previously unrecognized mechanism through which UC-MSCs facilitate renal repair, so as to induce global metabolic reprogramming of damaged tubular cells to sustain energy supply.Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.

Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression.

PubMed

Nezu, Masahiro; Souma, Tomokazu; Yu, Lei; Suzuki, Takafumi; Saigusa, Daisuke; Ito, Sadayoshi; Suzuki, Norio; Yamamoto, Masayuki

2017-02-01

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Renal function in hepatosplenic schistosomiasis--an assessment of renal tubular disorders.

PubMed

Duarte, Daniella Bezerra; Vanderlei, Lucas Alexandre; Bispo, Raianne Kívia de Azevêdo; Pinheiro, Maria Eliete; da Silva, Geraldo Bezerra; Martins, Alice Maria Costa; Meneses, Gdayllon Cavalcante; Daher, Elizabeth De Francesco

2014-01-01

Renal involvement in Schistosoma mansoni infection is not well studied. The aim of this study is to investigate the occurrence of renal abnormalities in patients with hepatosplenic schistosomiasis (HSS), especially renal tubular disorders. This is a cross-sectional study with 20 consecutive patients with HSS followed in a medical center in Maceió, Alagoas, Brazil. Urinary acidification and concentration tests were performed using calcium chloride (CaCl2) after a 12-h period of water and food deprivation. The biomarker monocyte chemoattractant protein 1 (MCP-1) was quantified in urine. Fractional excretion of sodium (FENa+), transtubular potassium gradient (TTKG) and solute-free water reabsorption (TcH2O) were calculated. The HSS group was compared to a group of 17 healthy volunteers. Patients' mean age and gender were similar to controls. Urinary acidification deficit was found in 45% of HSS patients. Urinary osmolality was significantly lower in HSS patients (588 ± 112 vs. 764 ± 165 mOsm/kg, p = 0,001) after a 12-h period of water deprivation. TcH2O was lower in HSS patients (0.72 ± 0.5 vs. 1.1 ± 0.3, p = 0.04). Urinary concentration deficit was found in 85% of HSS patients. The values of MCP-1 were higher in HSS group than in control group (122 ± 134 vs. 40 ± 28 pg/mg-Cr, p = 0.01) and positively correlated with the values of microalbuminuria and proteinuria. HSS is associated with important kidney dysfunction. The main abnormalities found were urinary concentrating ability and incomplete distal acidification defect, demonstrating the occurrence of tubular dysfunction. There was also an increase in urinary MCP-1, which appears to be a more sensitive marker of renal damage than urinary albumin excretion rate.

Distal renal tubular acidosis and hepatic lipidosis in a cat.

PubMed

Brown, S A; Spyridakis, L K; Crowell, W A

1986-11-15

Clinical and laboratory evidence of hepatic failure was found in a chronically anorectic cat. Simultaneous blood and urine pH determinations established a diagnosis of distal renal tubular acidosis. The cat did not respond to treatment. Necropsy revealed distal tubular nephrosis and hepatic lipidosis. The finding of distal renal tubular acidosis in a cat with hepatic lipidosis emphasizes the importance of complete evaluation of acid-base disorders in patients.

The rebirth of interest in renal tubular function.

PubMed

Lowenstein, Jerome; Grantham, Jared J

2016-06-01

The measurement of glomerular filtration rate by the clearance of inulin or creatinine has evolved over the past 50 years into an estimated value based solely on plasma creatinine concentration. We have examined some of the misconceptions and misunderstandings of the classification of renal disease and its course, which have followed this evolution. Furthermore, renal plasma flow and tubular function, which in the past were estimated by the clearance of the exogenous aryl amine, para-aminohippurate, are no longer measured. Over the past decade, studies in experimental animals with reduced nephron mass and in patients with reduced renal function have identified small gut-derived, protein-bound uremic retention solutes ("uremic toxins") that are poorly filtered but are secreted into the lumen by organic anion transporters (OATs) in the proximal renal tubule. These are not effectively removed by conventional hemodialysis or peritoneal dialysis. Residual renal function, urine produced in patients with advanced renal failure or undergoing dialysis treatment, may represent, at least in part, secretion of fluid and uremic toxins, such as indoxyl sulfate, mediated by proximal tubule OATs and might serve as a useful survival function. In light of this new evidence of the physiological role of proximal tubule OATs, we suggest that measurement of renal tubular function and renal plasma flow may be of considerable value in understanding and managing chronic kidney disease. Data obtained in normal subjects indicate that renal plasma flow and renal tubular function might be measured by the clearance of the endogenous aryl amine, hippurate. Copyright © 2016 the American Physiological Society.

New Markers of Inflammation and Tubular Damage in Children with Chronic Kidney Disease.

PubMed

Musiał, Kinga; Bargenda, Agnieszka; Drożdż, Dorota; Zwolińska, Danuta

2017-01-01

Monocyte chemoattractant protein- (MCP-) 1, macrophage colony-stimulating factor (MCSF), and neopterin are connected with monocyte migration and transition into macrophages, leading to fibrosis and tubular damage in the course of CKD. The aim of the study was to analyze the applicability of urinary fractional excretion (FE) of MCP1, MCSF, and neopterin, as markers of inflammation and tubular damage, in children with CKD. The study group consisted of 61 children with CKD stages 1-5 and 23 age-matched controls. The serum and urine concentrations of MCP1, MCSF, and neopterin were assessed by ELISA and then the fractional excretion (FE) was calculated. FE MCSF and neopterin values exceeded 1% already in controls. FE MCSF rose significantly since CKD stages 1-2, FE neopterin since CKD stages 3-5. FE MCP1 was below 1% in healthy controls and in CKD stages 1-2, then increased significantly in CKD stages 3-5. The FE MCP-1 values show that inflammation precedes the tubular dysfunction. FE MCSF and FE neopterin may be considered new markers of the renal parenchyma progressive damage. Fractional excretion may become a useful tool in the assessment of inflammation and tubular damage in children with CKD.

Developmental changes in renal tubular transport - An overview

PubMed Central

Gattineni, Jyothsna; Baum, Michel

2013-01-01

The adult kidney maintains a constant volume and composition of extracellular fluid despite changes in water and salt intake. The neonate is born with a kidney that has a small fraction of the glomerular filtration rate of the adult and immature tubules that function at a lower capacity than that of the mature animal. None the less, the neonate is also able to maintain a constant extracellular fluid volume and composition. Postnatal renal tubular development was once thought to be due to an increase in the transporter abundance to meet the developmental increase in glomerular filtration rate. However, postnatal renal development of each nephron segment is quite complex. There are isoform changes of several transporters as well as developmental changes in signal transduction that affect the capacity of renal tubules to reabsorb solutes and water. This review will discuss neonatal tubular function with an emphasis on the differences that have been found between the neonate and adult. We will also discuss some of the factors that are responsible for the maturational changes in tubular transport that occur during postnatal renal development. PMID:24253590

Developmental changes in renal tubular transport-an overview.

PubMed

Gattineni, Jyothsna; Baum, Michel

2015-12-01

The adult kidney maintains a constant volume and composition of extracellular fluid despite changes in water and salt intake. The neonate is born with a kidney that has a small fraction of the glomerular filtration rate of the adult and immature tubules that function at a lower capacity than that of the mature animal. Nonetheless, the neonate is also able to maintain a constant extracellular fluid volume and composition. Postnatal renal tubular development was once thought to be due to an increase in the transporter abundance to meet the developmental increase in glomerular filtration rate. However, postnatal renal development of each nephron segment is quite complex. There are isoform changes of several transporters as well as developmental changes in signal transduction that affect the capacity of renal tubules to reabsorb solutes and water. This review will discuss neonatal tubular function with an emphasis on the differences that have been found between the neonate and adult. We will also discuss some of the factors that are responsible for the maturational changes in tubular transport that occur during postnatal renal development.

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney.

PubMed

Duan, Xiaolu; Kong, Zhenzhen; Mai, Xin; Lan, Yu; Liu, Yang; Yang, Zhou; Zhao, Zhijian; Deng, Tuo; Zeng, Tao; Cai, Chao; Li, Shujue; Zhong, Wen; Wu, Wenqi; Zeng, Guohua

2018-06-01

Hyperoxaluria-induced oxidative injury of renal tubular epithelial cell is a casual and essential factor in kidney calcium oxalate (CaOx) stone formation. Autophagy has been shown to be critical for the regulation of oxidative stress-induced renal tubular injury; however, little is known about its role in kidney CaOx stone formation. In the present study, we found that the autophagy antagonist chloroquine could significantly attenuate oxalate-induced autophagy activation, oxidative injury and mitochondrial damage of renal tubular cells in vitro and in vivo, as well as hyperoxaluria-induced CaOx crystals depositions in rat kidney, whereas the autophagy agonist rapamycin exerted contrasting effects. In addition, oxalate-induced p38 phosphorylation was significantly attenuated by chloroquine pretreatment but was markedly enhanced by rapamycin pretreatment, whereas the protective effect of chloroquine on rat renal tubular cell oxidative injury was partly reversed by a p38 protein kinase activator anisomycin. Furthermore, the knockdown of Beclin1 represented similar effects to chloroquine on oxalate-induced cell oxidative injury and p38 phosphorylation in vitro. Taken together, our results revealed that autophagy inhibition could attenuate oxalate-induced oxidative injury of renal tubular cell and CaOx crystal depositions in the rat kidney via, at least in part, inhibiting the activation of p38 signaling pathway, thus representing a novel role of autophagy in the regulation of oxalate-induced renal oxidative injury and CaOx crystal depositions for the first time. Copyright © 2018. Published by Elsevier B.V.

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury.

PubMed

Pressly, Jeffrey D; Mustafa, Suni M; Adibi, Ammaar H; Alghamdi, Sahar; Pandey, Pankaj; Roy, Kuldeep K; Doerksen, Robert J; Moore, Bob M; Park, Frank

2018-02-01

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Diabetes and renal tubular cell apoptosis

PubMed Central

Habib, Samy L

2013-01-01

Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose induces apoptosis is not fully understood. Apoptosis of tubular epithelial cells is a major feature of diabetic kidney disease, and hyperglycemia triggers the generation of free radicals and oxidant stress in tubular cells. Hyperglycemia and high glucose in vitro also lead to apoptosis, a form of programmed cell death. High glucose similar to those seen with hyperglycemia in people with diabetes mellitus, lead to accelerated apoptosis, a form of programmed cell death characterized by cell shrinkage, chromatin condensation and DNA fragmentation, in variety of cell types, including renal proximal tubular epithelial cells. PMID:23593533

Diabetes and renal tubular cell apoptosis.

PubMed

Habib, Samy L

2013-04-15

Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose induces apoptosis is not fully understood. Apoptosis of tubular epithelial cells is a major feature of diabetic kidney disease, and hyperglycemia triggers the generation of free radicals and oxidant stress in tubular cells. Hyperglycemia and high glucose in vitro also lead to apoptosis, a form of programmed cell death. High glucose similar to those seen with hyperglycemia in people with diabetes mellitus, lead to accelerated apoptosis, a form of programmed cell death characterized by cell shrinkage, chromatin condensation and DNA fragmentation, in variety of cell types, including renal proximal tubular epithelial cells.

Genetics Home Reference: renal tubular dysgenesis

MedlinePlus

... genetic condition? Genetic and Rare Diseases Information Center Frequency Renal tubular dysgenesis is a rare disorder, but ... of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA HONCode ...

Renal tubular function in children with tyrosinaemia type I treated with nitisinone.

PubMed

Santra, S; Preece, M A; Hulton, S-A; McKiernan, P J

2008-06-01

Tyrosinaemia type I (TTI) is an inherited deficiency in the enzyme fumarylacetoacetate hydrolase and is frequently complicated by renal tubular dysfunction which may persist in some patients after hepatic transplantation. Nitisinone has revolutionized the management of TTI but its effect on renal tubular dysfunction has not been described in a large cohort of patients. To document the incidence and progression of renal tubular dysfunction in children with TTI treated with nitisinone at a single centre. Twenty-one patients with TTI from a single centre were treated with nitisinone for at least 12 months. Median age at first treatment was 17 weeks (range 1 week to 27 months). Nine patients (43%) presented in acute liver failure, seven (33%) had a chronic presentation and five (24%) were detected pre-clinically. A retrospective case analysis of plasma phosphate, urinary protein/creatinine ratio and tubular reabsorption of phosphate was performed for all patients as markers of tubular function. Renal ultrasounds were examined for evidence of nephrocalcinosis and where available, skeletal radiographs for rickets. All patients had biochemical evidence of renal tubular dysfunction at presentation. After nitisinone and dietary treatment were started, all three markers normalized within one year. Four children had clinical rickets at presentation (which improved), of whom one had nephrocalcinosis, which did not reverse on nitisinone. No child redeveloped tubular dysfunction after commencing nitisinone. All patients with TTI had evidence of tubular dysfunction at presentation and in all cases this resolved with nitisinone and dietary control. The tubulopathy associated with TTI is reversible.

Comorbid renal tubular damage and hypoalbuminemia exacerbate cardiac prognosis in patients with chronic heart failure.

PubMed

Otaki, Yoichiro; Watanabe, Tetsu; Takahashi, Hiroki; Funayama, Akira; Kinoshita, Daisuke; Yokoyama, Miyuki; Takahashi, Tetsuya; Nishiyama, Satoshi; Arimoto, Takanori; Shishido, Tetsuro; Miyamoto, Takuya; Konta, Tsuneo; Kubota, Isao

2016-02-01

Renal tubular damage (RTD) and hypoalbuminemia are risks for poor prognosis in patients with chronic heart failure (CHF). Renal tubules play a pivotal role in amino acid and albumin reabsorption, which maintain serum albumin levels. The aims of the present study were to (1) examine the association of RTD with hypoalbuminemia, and (2) assess the prognostic importance of comorbid RTD and hypoalbuminemia in patients with CHF. We measured N-acetyl-β-D-glucosamidase (NAG) levels and the urinary β2-microglobulin to creatinine ratio (UBCR) in 456 patients with CHF. RTD was defined as UBCR ≥ 300 μg/g or NAG ≥ 14.2 U/g. There were moderate correlations between RTD markers and serum albumin (NAG, r = -0.428, P < 0.0001; UBCR, r = -0.399, P < 0.0001). Multivariate logistic analysis showed that RTD was significantly related to hypoalbuminemia in patients with CHF. There were 134 cardiac events during a median period of 808 days. The comorbidity of RTD and hypoalbuminemia was increased with advancing New York Heart Association functional class. Multivariate Cox proportional hazard regression analysis showed that the presence of RTD and hypoalbuminemia was associated with cardiac events. The net reclassification index was significantly improved by adding RTD and hypoalbuminemia to the basic risk factors. Comorbid RTD and hypoalbuminemia are frequently observed and increase the risk for extremely poor outcome in patients with CHF.

Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cárdenas-González, Mariana C.; Del Razo, Luz M.; Barrera-Chimal, Jonatan

2013-11-01

Fluoride is usually found in groundwater at a very wide range of concentration between 0.5 and 25 ppm. At present, few studies have assessed the renal effects of fluoride at environmentally relevant concentrations. Furthermore, most of these studies have used insensitive and nonspecific biomarkers of kidney injury. The aim of this study was to use early and sensitive biomarkers to evaluate kidney injury after fluoride exposure to environmentally relevant concentrations. Recently weaned male Wistar rats were exposed to low (15 ppm) and high (50 ppm) fluoride concentrations in drinking water for a period of 40 days. At the end ofmore » the exposure period, kidney injury biomarkers were measured in urine and renal mRNA expression levels were assessed by real time RT-PCR. Our results showed that the urinary kidney injury molecule (Kim-1), clusterin (Clu), osteopontin (OPN) and heat shock protein 72 excretion rate significantly increased in the group exposed to the high fluoride concentration. Accordingly, fluoride exposure increased renal Kim-1, Clu and OPN mRNA expression levels. Moreover, there was a significant dose-dependent increase in urinary β-2-microglobulin and cystatin-C excretion rate. Additionally, a tendency towards a dose dependent increase of tubular damage in the histopathological light microscopy findings confirmed the preferential impact of fluoride on the tubular structure. All of these changes occurred at early stages in which, the renal function was not altered. In conclusion using early and sensitive biomarkers of kidney injury, we were able to found proximal tubular alterations in rats sub-chronically exposed to fluoride. - Highlights: • Exposure to low concentrations of fluoride induced proximal tubular injury • Increase in urinary Kim-1, Clu, OPN and Hsp72 in 50 ppm fluoride-exposed group • Increase in urinary B2M and CysC in 15 and 50 ppm fluoride-exposed groups • Fluoride exposure increased renal Kim, Clu and OPN mRNA expression

[A comparative study of the renal damage produced after the extracorporeal shock wave lithotripsy according to the lithiasis location].

PubMed

Cancho Gil, Ma J; Díz Rodríguez, R; Vírseda Chamorro, M; Alpuente Román, C; Cabrera Cabrera, J A; Paños Lozano, P

2005-04-01

The Extracorporeal shock waves lithotripsy (ESWL) is fundamental in the treatment of lithiasis. However, there are evidences that it can produce renal damage. The objective of our study is to determine the degree of affectation of the glomerular and tubular function after ESWL, and the influence of the lithiasis location on the type of renal damage. A prospective longitudinal study was carried out in 14 patients with normal renal function subjected to ESWL. We determined the basal level, and the levels at the 24 hours, at the 4th and the 10th day post ESWL of: microalbuminuria (MA) (that values the glomerular function), and N-acetyl glucosamide (NAG) and alanine aminopeptidase (AAP), (that value the tubular function). The basal levels of of MA, NAG and AAP didn't show significant differences in connection with the localization of the stones. A significant increase was observed of the three parameters only 24 hours post ESWL. No significant differences were observed between the variation of the microalbuminuria levels, AAP and NAG and the treatment in relation to the localization of the stones. It exists a glomerular and tubular damage after ESWL. This damage is not related with the pelvic or calicial location of the stones. In patient with previous normal renal function, the renal damage recovers at the 4th day post ESWL.

Mechanism of intracellular signal transduction during injury of renal tubular cells induced by postasphyxial serum in neonates with asphyxia.

PubMed

Zhao, Jin; Dong, Wen-Bin; Li, Peng-yun; Deng, Chun-liang

2009-01-01

Renal injury is a severe and extremely common complication that occurs early in neonates with asphyxia. Reperfusion injury has been suggested as the cause of kidney damage during resuscitation of neonatal asphyxia. Previous studies have demonstrated that postasphyxial serum from neonates with asphyxia may result in apoptosis of renal tubular cells. However, the mechanisms that mediate renal tubular cell apoptosis induced by postasphyxial serum remain poorly understood. In this report we investigate the intracellular signal transduction mechanisms that operate during injury of renal tubular cells induced by postasphyxial serum in neonates. Cultured human renal proximal tubular cells HK-2 cell were exposed to 10% fetal calf serum (normal control), 20% postasphyxial serum or 20% postasphyxial serum with pyrrolidine dithiocarbamate (PDTC). The expression of both BAD and BAX in the cytoplasm was detected by immunohistochemistry. The mitochondria membrane potential (Deltapsim) was examined by confocal microscopy, and the release of the apoptogenic mitochondrial proteins cytochrome C and AIF was assessed by Western blot analysis. Loss of mitochondria membrane potential was detected in HK-2 cells treated with 20% postasphyxial serum as compared to cells in normal serum or PTDC-pretreated cells in 20% postasphyxial serum. A significant increase of Bad and Bax protein expression was also detected, along with the release of cytochrome C and AIF from mitochondria to cytosol in the postasphyxial serum treated cells, but not in the normal or PTDC-pretreated control cells. Our findings suggest that postasphyxial serum may induce renal tubular cell apoptosis through the mitochondrial pathway, and its intracellular signal transduction mechanism includes the activation of nuclear factor-kappaB. Copyright 2009 S. Karger AG, Basel.

Hyperammonemia associated with distal renal tubular acidosis or urinary tract infection: a systematic review.

PubMed

Clericetti, Caterina M; Milani, Gregorio P; Lava, Sebastiano A G; Bianchetti, Mario G; Simonetti, Giacomo D; Giannini, Olivier

2018-03-01

Hyperammonemia usually results from an inborn error of metabolism or from an advanced liver disease. Individual case reports suggest that both distal renal tubular acidosis and urinary tract infection may also result in hyperammonemia. A systematic review of the literature on hyperammonemia secondary to distal renal tubular acidosis and urinary tract infection was conducted. We identified 39 reports on distal renal tubular acidosis or urinary tract infections in association with hyperammonemia published between 1980 and 2017. Hyperammonemia was detected in 13 children with distal renal tubular acidosis and in one adult patient with distal renal tubular acidosis secondary to primary hyperparathyroidism. In these patients a negative relationship was observed between circulating ammonia and bicarbonate levels (P < 0.05). In 31 patients (19 children, 12 adults), an acute urinary tract infection was complicated by acute hyperammonemia and symptoms and signs of acute neuronal dysfunction, such as an altered level of consciousness, convulsions and asterixis, often associated with signs of brain edema, such as anorexia and vomiting. Urea-splitting bacteria were isolated in 28 of the 31 cases. The urinary tract was anatomically or functionally abnormal in 30 of these patients. This study reveals that both altered distal renal tubular acidification and urinary tract infection may be associated with relevant hyperammonemia in both children and adults.

Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro by activating autophagy

PubMed Central

Liu, Hong; Gu, Liu-bao; Tu, Yue; Hu, Hao; Huang, Yan-ru; Sun, Wei

2016-01-01

Aim: A previous report shows that emodin extracted from the Chinese herbs rhubarb and giant knotweed rhizome can ameliorate the anticancer drug cisplatin-induced injury of HEK293 cells. In this study, we investigated whether and how emodin could protect renal tubular epithelial cells against cisplatin-induced nephrotoxicity in vitro. Methods: The viability and apoptosis of normal rat renal tubular epithelial cells (NRK-52E) were detected using formazan assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy maker LC3 I/II, and AMPK/mTOR signaling pathway-related proteins were measured with Western blot analysis. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy. Results: Cisplatin (10-50 μmol/L) dose-dependently induced cell damage and apoptosis in NRK-52E cells, whereas emodin (10 and 100 μmol/L) significantly ameliorated cisplatin-induced cell damage, apoptosis and caspase-3 cleavage. Emodin dose-dependently increased LC3-II levels and induced RFP-LC3-containing punctate structures in NRK-52E cells. Furthermore, the protective effects of emodin were abolished by bafilomycin A1 (10 nmol/L), and mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 μmol/L) not only abolished emodin-induced autophagy activation, but also emodin-induced anti-apoptotic effects. Conclusion: Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro through modulating the AMPK/mTOR signaling pathways and activating autophagy. Emodin may have therapeutic potential for the prevention of cisplatin-induced nephrotoxicity. PMID:26775661

Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro by activating autophagy.

PubMed

Liu, Hong; Gu, Liu-bao; Tu, Yue; Hu, Hao; Huang, Yan-ru; Sun, Wei

2016-02-01

A previous report shows that emodin extracted from the Chinese herbs rhubarb and giant knotweed rhizome can ameliorate the anticancer drug cisplatin-induced injury of HEK293 cells. In this study, we investigated whether and how emodin could protect renal tubular epithelial cells against cisplatin-induced nephrotoxicity in vitro. The viability and apoptosis of normal rat renal tubular epithelial cells (NRK-52E) were detected using formazan assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy maker LC3 I/II, and AMPK/mTOR signaling pathway-related proteins were measured with Western blot analysis. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy. Cisplatin (10-50 μmol/L) dose-dependently induced cell damage and apoptosis in NRK-52E cells, whereas emodin (10 and 100 μmol/L) significantly ameliorated cisplatin-induced cell damage, apoptosis and caspase-3 cleavage. Emodin dose-dependently increased LC3-II levels and induced RFP-LC3-containing punctate structures in NRK-52E cells. Furthermore, the protective effects of emodin were abolished by bafilomycin A1 (10 nmol/L), and mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 μmol/L) not only abolished emodin-induced autophagy activation, but also emodin-induced anti-apoptotic effects. Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro through modulating the AMPK/mTOR signaling pathways and activating autophagy. Emodin may have therapeutic potential for the prevention of cisplatin-induced nephrotoxicity.

Renal Tubular Acidosis in Patients with Primary Sjögren's Syndrome.

PubMed

Jung, Su Woong; Park, Eun Ji; Kim, Jin Sug; Lee, Tae Won; Ihm, Chun Gyoo; Lee, Sang Ho; Moon, Ju-Young; Kim, Yang Gyun; Jeong, Kyung Hwan

2017-09-01

Primary Sjögren's syndrome (pSS) is characterized by lymphocytic infiltration of the exocrine glands resulting in decreased saliva and tear production. It uncommonly involves the kidneys in various forms, including tubulointerstitial nephritis, renal tubular acidosis, Fanconi syndrome, and rarely glomerulonephritis. Its clinical symptoms include muscle weakness, periodic paralysis, and bone pain due to metabolic acidosis and electrolyte imbalance. Herein, we describe the cases of two women with pSS whose presenting symptoms involve the kidneys. They had hypokalemia and normal anion gap metabolic acidosis due to distal renal tubular acidosis and positive anti-SS-A and anti-SS-B autoantibodies. Since one of them experienced femoral fracture due to osteomalacia secondary to renal tubular acidosis, an earlier diagnosis of pSS is important in preventing serious complications.

Glomerular and tubular damage markers in individuals with progressive albuminuria.

PubMed

Nauta, Ferdau L; Scheven, Lieneke; Meijer, Esther; van Oeveren, Wim; de Jong, Paul E; Bakker, Stephan J L; Gansevoort, Ron T

2013-07-01

Albuminuria is associated with risk for renal and cardiovascular disease. It is difficult to predict which persons will progress in albuminuria. This study investigated whether assessment of urinary markers associated with damage to different parts of the nephron may help identify individuals that will progress in albuminuria. Individuals were selected from a prospective community-based cohort study with serial follow-up and defined as "progressors" if they belonged to the quintile of participants with the most rapid annual increase in albuminuria, and reached an albuminuria ≥150 mg/d during follow-up. Patients with known renal disease or macroalbuminuria at baseline were excluded. Each progressor was matched to two control participants, based on baseline albuminuria, age, and sex. Furthermore, damage markers were measured in a separate set of healthy individuals. After a median follow-up of 8.6 years, 183 of 8394 participants met the criteria for progressive albuminuria. Baseline clinical characteristics were comparable between progressors and matched controls (n=366). Both had higher baseline albuminuria than the overall population. Urinary excretion of the glomerular damage marker IgG was significantly higher in progressors, whereas urinary excretion of proximal tubular damage markers and inflammatory markers was lower in these individuals compared with controls. Healthy individuals (n=109) had the lowest values for all urinary damage markers measured. These data suggest that albuminuria associated with markers of glomerular damage is more likely to progress, whereas albuminuria associated with markers of tubulointerstitial damage is more likely to remain stable.

[Acute renal failure and proximal renal tubular dysfuntion in a patient with acquired immunodeficiency syndrome treated with tenofovir].

PubMed

de la Prada, F J; Prados, A M; Tugores, A; Uriol, M; Saus, C; Morey, A

2006-01-01

Tenofovir, a new nucleotide reverse transcriptase inhibitor that has good antiviral activity against drug-resistant strains of HIV, is structurally similar to cidofovir and adefovir and seems to be less nephrotoxic. Nephrotoxicity of cidofovir and adefovir is well established and they have been associated with increase for acute renal insufficiency due to tubular toxicity, possibly induced via mitochondrial deplection. Tenofovir has little mithocondrial toxicity in in vitro assays and early clinical studies. However some cases of renal tubular dysfuntion and renal failure related to tenofovir treatment have been published recently. Increased plasma concentrations of didanosine were observed after the adition of tenofovir and protease inhibitors can interact with the renal transport of organic anions leading to proximal tubular intracellular accumulation of tenofovir, yield Fanconi syndrome-type tubulopathy. We present a case in wich acute renal failure and proximal tubular dysfunction developed after therapy with tenofovir in a patiente with HIV who had suffered from complications of didanosine treatment. Although nephrotoxicity certainly occurs much less frequently with tenofovir that it does with other nuclotide analogues, use of tenofovir by patients with underlying renal disfuntion, for longer durations and/or associated with didanosine or lopinavir-ritonavir, might be associated with renal toxicity. Patients receiving tenofovir must be monitored for sings of tubulopathy with simple tests such us glycosuria, phosphaturia, proteinuria, phosphoremia and renal function, as well as assessment for signs of mithocondrial toxicity when a nucleoside analogue is being administered, and therapy should be stopped to avoid the risk of definitive renal failure.

Factor h and properdin recognize different epitopes on renal tubular epithelial heparan sulfate.

PubMed

Zaferani, Azadeh; Vivès, Romain R; van der Pol, Pieter; Navis, Gerjan J; Daha, Mohamed R; van Kooten, Cees; Lortat-Jacob, Hugues; Seelen, Marc A; van den Born, Jacob

2012-09-07

During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (K(D) values of 32 and 93 nm, respectively). Using a library of HS-like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement-derived tubular injury in proteinuric renal diseases.

Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans

NASA Technical Reports Server (NTRS)

Nagashima, K.; Wu, J.; Kavouras, S. A.; Mack, G. W.

2001-01-01

We tested the hypothesis that renal tubular Na(+) reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O(2) uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na(+) in the proximal tubules was higher in Ex than in C (P < 0.05). Saline loading decreased fractional tubular reabsorption of Na(+) from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P < 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na(+) reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na(+) reabsorption during saline infusion 24 h after exercise.

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

PubMed Central

Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C.; Khadayate, Sanjay; Mas, Valeria R.; Nitsch, Dorothea D.; Wang, Zhen; Norman, Jill T.; Wilcox, Christopher S.; Wheeler, David C.; Leiper, James

2015-01-01

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule–specific Ddah1 knockout (Ddah1PT−/−) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1PT−/− mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. PMID:25855779

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.

PubMed

Tomlinson, James A P; Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C; Khadayate, Sanjay; Mas, Valeria R; Nitsch, Dorothea D; Wang, Zhen; Norman, Jill T; Wilcox, Christopher S; Wheeler, David C; Leiper, James

2015-12-01

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1(PT-/-)) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1(PT-/-) mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. Copyright © 2015 by the American Society of Nephrology.

Glomerular and Tubular Damage Markers in Individuals with Progressive Albuminuria

PubMed Central

Nauta, Ferdau L.; Scheven, Lieneke; Meijer, Esther; van Oeveren, Wim; de Jong, Paul E.; Bakker, Stephan J.L.

2013-01-01

Summary Background and objectives Albuminuria is associated with risk for renal and cardiovascular disease. It is difficult to predict which persons will progress in albuminuria. This study investigated whether assessment of urinary markers associated with damage to different parts of the nephron may help identify individuals that will progress in albuminuria. Design, setting, participants, & measurements Individuals were selected from a prospective community-based cohort study with serial follow-up and defined as “progressors” if they belonged to the quintile of participants with the most rapid annual increase in albuminuria, and reached an albuminuria ≥150 mg/d during follow-up. Patients with known renal disease or macroalbuminuria at baseline were excluded. Each progressor was matched to two control participants, based on baseline albuminuria, age, and sex. Furthermore, damage markers were measured in a separate set of healthy individuals. Results After a median follow-up of 8.6 years, 183 of 8394 participants met the criteria for progressive albuminuria. Baseline clinical characteristics were comparable between progressors and matched controls (n=366). Both had higher baseline albuminuria than the overall population. Urinary excretion of the glomerular damage marker IgG was significantly higher in progressors, whereas urinary excretion of proximal tubular damage markers and inflammatory markers was lower in these individuals compared with controls. Healthy individuals (n=109) had the lowest values for all urinary damage markers measured. Conclusions These data suggest that albuminuria associated with markers of glomerular damage is more likely to progress, whereas albuminuria associated with markers of tubulointerstitial damage is more likely to remain stable. PMID:23539232

Distal Renal Tubular Acidosis and Calcium Nephrolithiasis

NASA Astrophysics Data System (ADS)

Moe, Orson W.; Fuster, Daniel G.; Xie, Xiao-Song

2008-09-01

Calcium stones are commonly encountered in patients with congenital distal renal tubular acidosis, a disease of renal acidification caused by mutations in either the vacuolar H+-ATPase (B1 or a4 subunit), anion exchanger-1, or carbonic anhydrase II. Based on the existing database, we present two hypotheses. First, heterozygotes with mutations in B1 subunit of H+-ATPase are not normal but may harbor biochemical abnormalities such as renal acidification defects, hypercalciuria, and hypocitraturia which can predispose them to kidney stone formation. Second, we propose at least two mechanisms by which mutant B1 subunit can impair H+-ATPase: defective pump assembly and defective pump activity.

Reference values of renal tubular function tests are dependent on age and kidney function.

PubMed

Bech, Anneke P; Wetzels, Jack F M; Nijenhuis, Tom

2017-12-01

Electrolyte disorders due to tubular disorders are rare, and knowledge about validated clinical diagnostic tools such as tubular function tests is sparse. Reference values for tubular function tests are based on studies with small sample size in young healthy volunteers. Patients with tubular disorders, however, frequently are older and can have a compromised renal function. We therefore evaluated four tubular function tests in individuals with different ages and renal function. We performed furosemide, thiazide, furosemide-fludrocortisone, and desmopressin tests in healthy individuals aged 18-50 years, healthy individuals aged more than 50 years and individuals with compromised renal function. For each tubular function test we included 10 individuals per group. The responses in young healthy individuals were in line with previously reported values in literature. The maximal increase in fractional chloride excretion after furosemide was below the lower limit of young healthy individuals in 5/10 older subjects and in 2/10 patients with compromised renal function. The maximal increase in fractional chloride excretion after thiazide was below the lower limit of young healthy individuals in 6/10 older subjects and in 7/10 patients with compromised renal function. Median maximal urine osmolality after desmopressin was 1002 mosmol/kg H 2 O in young healthy individuals, 820 mosmol/kg H 2 O in older subjects and 624 mosmol/kg H 2 O in patients with compromised renal function. Reference values for tubular function tests obtained in young healthy adults thus cannot simply be extrapolated to older patients or patients with compromised kidney function. Larger validation studies are needed to define true reference values in these patient categories. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Kidney specific protein-positive cells derived from embryonic stem cells reproduce tubular structures in vitro and differentiate into renal tubular cells.

PubMed

Morizane, Ryuji; Monkawa, Toshiaki; Fujii, Shizuka; Yamaguchi, Shintaro; Homma, Koichiro; Matsuzaki, Yumi; Okano, Hideyuki; Itoh, Hiroshi

2014-01-01

Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.

Medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome.

PubMed

Karunarathne, Suneth; Udayakumara, Yapa; Govindapala, Dumitha; Fernando, Harshini

2012-07-26

Medullary nephrocalcinosis and distal renal tubular acidosis are closely associated and each can lead to the other. These clinical entities are rare in patients with nephrotic syndrome and polycythaemia is an unusual finding in such patients. We describe the presence of medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome due to minimal change disease. Proposed mechanisms of polycythaemia in patients with nephrotic syndrome and distal renal tubular acidosis include, increased erythropoietin production and secretion of interleukin 8 which in turn stimulate erythropoiesis. A 22 year old Sri Lankan Sinhala male with nephrotic syndrome due to minimal change disease was investigated for incidentally detected polycythaemia. Investigations revealed the presence of renal tubular acidosis type I and medullary nephrocalcinosis. Despite extensive investigation, a definite cause for polycythaemia was not found in this patient. Treatment with potassium and bicarbonate supplementation with potassium citrate led to correction of acidosis thereby avoiding the progression of nephrocalcinosis and harmful effects of chronic acidosis. The constellation of clinical and biochemical findings in this patient is unique but the pathogenesis of erythrocytosis is not clearly explained. The proposed mechanisms for erythrocytosis in other patients with proteinuria include increased erythropoietin secretion due to renal hypoxia and increased secretion of interleukin 8 from the kidney. This case illustrates that there may exist hitherto unknown connections between tubular and glomerular dysfunction in patients with nephrotic syndrome.

[Case of distal renal tubular acidosis complicated with renal diabetes insipidus, showing aggravation of symptoms with occurrence of diabetes mellitus].

PubMed

Liu, Hexing; Tomoda, Fumihiro; Koike, Tsutomu; Ohara, Maiko; Nakagawa, Taizo; Kagitani, Satoshi; Inoue, Hiroshi

2011-01-01

We report herein a 27-year-old male case of inherited distal renal tubular acidosis complicated with renal diabetes insipidus, the symptoms of which were aggravated by the occurrence of diabetes mellitus. At 2 months after birth, he was diagnosed as having inherited distal renal tubular acidosis and thereafter supplementation of both potassium and alkali was started to treat his hypokalemia and metabolic acidosis. At the age of 4 years, calcification of the bilateral renal medulla was detected by computed tomography. Subsequently his urinary volume gradually increased and polyuria of approximately 4 L/day persisted. At the age of 27 years, he became fond of sugar-sweetened drinks and also often forgot to take the medicine. He was admitted to our hospital due to polyuria of more than 10 L day, muscle weakness and gait disturbance. Laboratory tests disclosed worsening of both hypokalemia and metabolic acidosis in addition to severe hyperglycemia. It seemed likely that occurrence of diabetes mellitus and cessation of medications can induce osmotic diuresis and aggravate hypokalemia and metabolic acidosis. Consequently, severe dehydration, hypokalemia-induced damage of his urinary concentration ability and enhancement of the renin angiotensin system occurred and thereby possibly worsened his hypokalemia and metabolic acidosis. As normalization of hyperglycemia and metabolic acidosis might have exacerbated hypokalemia further, dehydration and hypokalemia were treated first. Following intensive treatment, these abnormalities were improved, but polyuria persisted. Elevated plasma antidiuretic hormone (12.0 pg/mL) and deficit of renal responses to antidiuretic hormone suggested that the polyuria was attributable to the preexisting renal diabetes insipidus possibly caused by bilateral renal medulla calcification. Thiazide diuretic or nonsteroidal anti-inflammatory drugs were not effective for the treatment of diabetes insipidus in the present case.

Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers.

PubMed

Dhayat, Nasser A; Gradwell, Michael W; Pathare, Ganesh; Anderegg, Manuel; Schneider, Lisa; Luethi, David; Mattmann, Cedric; Moe, Orson W; Vogt, Bruno; Fuster, Daniel G

2017-09-07

Incomplete distal renal tubular acidosis is a well known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/fludrocortisone test was recently proposed as an alternative. Because of the lack of rigorous comparative studies, the validity of the furosemide/fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, nonprovocative parameters in predicting incomplete distal renal tubular acidosis has not been studied. We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/fludrocortisone testing. Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 8%. Sensitivity and specificity of the furosemide/fludrocortisone test were 77% and 85%, respectively, yielding a positive predictive value of 30% and a negative predictive value of 98%. Testing of several nonprovocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH <5.3 with a plasma potassium threshold >3.8 mEq/L yielded a negative predictive value of 98% with a sensitivity of 85% and a specificity of 77% for the diagnosis of incomplete distal renal tubular acidosis. The furosemide/fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of nonprovocative clinical

Tisp40 deficiency attenuates renal ischemia reperfusion injury induced apoptosis of tubular epithelial cells.

PubMed

Qin, Cong; Xiao, Chengcheng; Su, Yang; Zheng, Haizhou; Xu, Tao; Lu, Jingxiao; Luo, Pengcheng; Zhang, Jie

2017-10-01

Renal ischemia reperfusion (IR) is a major cause of acute kidney injury (AKI) and no effective treatments have been established. Tisp40 is a transcription factor of the CREB/ATF family and involves in cell apoptosis, proliferation and differentiation, but its role in renal IR remains unknown. Here, we investigated the role of Tisp40 in renal IR injury. In vivo, Tisp40 knockout (KO) and wild-type (WT) mice were subjected to thirty minutes of bilateral renal ischemia and 48h reperfusion, the blood and kidneys were harvested for analysis. In vitro, Tisp40 overexpression and vector cells were subjected to hypoxia/reoxygenation (HR), the apoptosis rate and the expressions of related proteins were measured. Following IR, the expressions of Tisp40 protein, serum creatinine (sCr), blood urea nitrogen (BUN) and apoptosis of tubular cells were significantly increased in WT mice. However, Tisp40 deficiency significantly attenuated the increase of sCr, BUN and apoptosis of tubular cells. Following HR, apoptosis of tubular cells was increased in Tisp40 overexpression cells compared with vector cells. Mechanistically, Tisp40 promoted the expressions of C/EBP homologous protein (CHOP), Bax and Cleaved caspase3 and suppressed the expression of Bcl-2 in renal IR injury. In conclusion, Tisp40 aggravates tubular cells apoptosis in renal IR injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Low molecular weight fucoidan protects renal tubular cells from injury induced by albumin overload.

PubMed

Jia, Yingli; Sun, Yi; Weng, Lin; Li, Yingjie; Zhang, Quanbin; Zhou, Hong; Yang, Baoxue

2016-08-22

Albuminuria is a causative and aggravating factor for progressive renal damage in chronic kidney disease (CKD). The aim of this study was to determine if low molecular weight fucoidan (LMWF) could protect renal function and tubular cells from albumin overload caused injury. Treatment with 10 mg/g bovine serum albumin caused renal dysfunction, morphological changes, and overexpression of inflammation and fibrosis associated proteins in 129S2/Sv mice. LMWF (100 mg/kg) protected against kidney injury and renal dysfunction with decreased blood creatinine by 34% and urea nitrogen by 25%, increased creatinine clearance by 48%, and decreased significantly urinary albumin concentration. In vitro proximal tubule epithelial cell (NRK-52E) model showed that LMWF dose-dependently inhibited overexpression of proinflammatory and profibrotic factors, oxidative stress and apoptosis caused by albumin overload. These experimental results indicate that LMWF protects against albumin overload caused renal injury by inhibiting inflammation, fibrosis, oxidative stress and apoptosis, which suggests that LMWF could be a promising candidate drug for preventing CKD.

Renal tubular leakage complicating microcephalic osteodysplastic primordial dwarfism.

PubMed Central

Eason, J; Hall, C M; Trounce, J Q

1995-01-01

We describe a male infant with phenotypic and radiological features of microcephalic osteodysplastic primordial dwarfism type I/III. He showed severe osteoporosis and biochemical derangement owing to renal tubular leakage, which has not previously been reported in this condition. He died aged 5 months. Images PMID:7783178

Adrenalectomy prevents renal ischemia-reperfusion injury.

PubMed

Ramírez, Victoria; Trujillo, Joyce; Valdes, Rafael; Uribe, Norma; Cruz, Cristino; Gamba, Gerardo; Bobadilla, Norma A

2009-10-01

Spironolactone treatment prevents renal damage induced by ischemia-reperfusion (I/R), suggesting that renoprotection conferred by spironolactone is mediated by mineralocorticoid receptor (MR) blockade. It is possible, however, that this effect is due to other mechanisms. Therefore, this study evaluated whether adrenalectomy prevented renal damage induced by I/R. Three groups of Wistar rats were studied: 1) a group subjected to a sham surgery, 2) a group subjected to bilateral I/R, and 3) a group of rats in which adrenal glands were removed 3 days before induction of I/R. As expected, I/R resulted in renal dysfunction and severe tubular injury that was associated with a significant increase in tubular damage markers. In contrast, there was no renal dysfunction or tubular injury in rats that were adrenalectomized before I/R. These effects were demonstrated by normalization of glomerular filtration rate, markers of oxidative stress, and tubular injury markers in adrenalectomized rats. The renoprotection observed was associated with the reestablishment of nitric oxide metabolites, increased endothelial nitric oxide synthase expression and its activating phosphorylation, as well as normalization of Rho-kinase expression and ET(A) mRNA levels. Our results show that aldosterone plays a central role in the pathogenesis of renal damage induced by I/R and that MR blockade may be a promising strategy that opens a new therapeutic option for preventing acute renal injury.

Ulinastatin inhibits renal tubular epithelial apoptosis and interstitial fibrosis in rats with unilateral ureteral obstruction.

PubMed

Zhang, Qing-Fang

2017-12-01

The effect of ulinastatin (UTI) on renal tubular epithelial apoptosis and interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) was investigated. A total of 18 male Wistar rats were randomly divided into the following 3 groups: The Sham group (n=6), the UUO group (n=6), and the UTI group (n=6). In the UUO and UTI groups, the left ureter was ligated to establish a UUO model. Starting from day 1 after surgery, an intervention treatment was performed using normal saline (1 ml/kg/d) and UTI (40,000 unit/kg/d). On day 7 after surgery, 6 rats from each group were sacrificed. In the Sham group, the left ureter was only freed, not ligated; after 7 days of abdominal closure, all of the rats were sacrificed. Blood samples were collected prior to sacrificing the animals to measure the blood urea nitrogen (BUN) and serum creatinine (Scr). The incidence of renal interstitial lesions on the obstruction side was observed by hematoxylin and eosin, and Masson staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and immunohistochemical detection of apoptosis regulator Bax (Bax), apoptosis regulator Bcl‑2 (Bcl‑2) and caspase‑3 were performed to observe the presence of renal tubular epithelial cell apoptosis. The UTI did not have a significant influence on the mouse BUN and Scr levels in any of the groups (P>0.05). Compared with that in the Sham group, renal tissue injury in the UUO group was significantly aggravated with renal tubular dilation, epithelial cell atrophy, renal interstitial inflammatory cell infiltration and fibrous tissue hyperplasia (P<0.01). Furthermore, the renal tubular epithelial TUNEL+ cell number and Bax and caspase‑3 levels were increased, and the expression of Bcl‑2 was decreased (P<0.01). Following the UTI treatment, the renal interstitial injury at the obstruction side was significantly attenuated (P<0.05), the renal tubular epithelial TUNEL+ cell number, and Bax and caspase‑3 levels

Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model

PubMed Central

Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

2016-01-01

The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet–fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms

Expression of a functional asialoglycoprotein receptor in human renal proximal tubular epithelial cells.

PubMed

Seow, Ying-ying T; Tan, Michelle G K; Woo, Keng Thye

2002-07-01

The asialoglycoprotein receptor (ASGPR) is a C lectin which binds and endocytoses serum glycoproteins. In humans, the ASGPR is shown mainly to occur in hepatocytes, but does occur extrahepatically in thyroid, in small and large intestines, and in the testis. In the kidney, there has been evidence both for and against its existence in mesangial cells. Standard light microscopy examination of renal tissue stained with an antibody against the ASGPR was performed. The mRNA expression for the ASGPR H1 and H2 subunits in primary human renal proximal tubular epithelial cells (RPTEC), in the human proximal tubular epithelial cell line HK2, and in human renal cortex was investigated using reverse-transcribed nested polymerase chain reaction. ASGPR protein expression as well as ligand binding and uptake were also examined using confocal microscopy and flow cytometry (fluorescence-activated cell sorting). Light microscopy of paraffin renal biopsy sections stained with a polyclonal antibody against the ASGPR showed proximal tubular epithelial cell staining of the cytoplasm and particularly in the basolateral region. Renal cortex and RPTEC specifically have mRNA for both H1 and H2 subunits of the ASGPR, but HK2 only expresses mRNA for H1. Using a monoclonal antibody, the presence of the ASGPR in RPTEC was shown by fluorescence-activated cell sorting and immunofluorescent staining. Specific binding and uptake of fluorescein isothiocyanate labelled asialofetuin which is a specific ASGPR ligand was also demonstrated in RPTEC. Primary renal proximal tubular epithelial cells have a functional ASGPR, consisting of the H1 and H2 subunits, that is capable of specific ligand binding and uptake. Copyright 2002 S. Karger AG, Basel

Distal Renal Tubular Acidosis in Infancy: A Bicarbonate Wasting State

ERIC Educational Resources Information Center

Rodriguez-Soriano, J.; And Others

1975-01-01

Studied were three unrelated infants with distal renal tubular acidosis (a condition characterized by an inability to acidify the urine to minimal pH levels resulting in the loss of bicarbonates). (DB)

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

PubMed Central

Giani, Jorge F.; Eriguchi, Masahiro; Bernstein, Ellen A.; Katsumata, Makoto; Shen, Xiao Z.; Li, Liang; McDonough, Alicia A.; Fuchs, Sebastien; Bernstein, Kenneth E.; Gonzalez-Villalobos, Romer A.

2017-01-01

Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension. PMID:27988209

Interferon-γ Reduces the Proliferation of Primed Human Renal Tubular Cells.

PubMed

García-Sánchez, Omar; López-Novoa, José Miguel; López-Hernández, Francisco J

2014-01-01

Chronic kidney disease (CKD) is a progressive deterioration of the kidney function, which may eventually lead to renal failure and the need for dialysis or kidney transplant. Whether initiated in the glomeruli or the tubuli, CKD is characterized by progressive nephron loss, for which the process of tubular deletion is of key importance. Tubular deletion results from tubular epithelial cell death and defective repair, leading to scarring of the renal parenchyma. Several cytokines and signaling pathways, including transforming growth factor-β (TGF-β) and the Fas pathway, have been shown to participate in vivo in tubular cell death. However, there is some controversy about their mode of action, since a direct effect on normal tubular cells has not been demonstrated. We hypothesized that epithelial cells would require specific priming to become sensitive to TGF-β or Fas stimulation and that this priming would be brought about by specific mediators found in the pathological scenario. Herein we studied whether the combined effect of several stimuli known to take part in CKD progression, namely TGF-β, tumor necrosis factor-α, interferon-γ (IFN-γ), and Fas stimulation, on primed resistant human tubular cells caused cell death or reduced proliferation. We demonstrate that these cytokines have no synergistic effect on the proliferation or viability of human kidney (HK2) cells. We also demonstrate that IFN-γ, but not the other stimuli, reduces the proliferation of cycloheximide-primed HK2 cells without affecting their viability. Our results point at a potentially important role of IFN-γ in defective repair, leading to nephron loss during CKD.

Neural control of renal tubular solute and water transport.

PubMed

DiBona, G F

1989-01-01

The neural control of renal tubular solute and water transport is recognized as an important physiological mechanism in the overall regulation of solute and water homeostasis by the mammalian organism. Recent studies have expanded the understanding of this mechanism concerning the transport of diverse solutes with beginning insight into the precise nature of the cellular transport processes involved. The modulatory roles of both circulating and intrarenal hormonal systems on the responses to alterations in the magnitude of efferent renal sympathetic nerve activity are being understood from the nerve terminal release of neurotransmitter to influences on cellular transport processes which determine the overall effect. When dietary sodium intake is normal or only modestly reduced, intact renal innervation is not essential for normal renal sodium conservation. However, when dietary sodium intake is severely restricted, there is maximum engagement of all mechanisms known to participate in renal sodium conservation and, under these conditions, intact renal innervation is essential for normal renal sodium conservation.

Cross talk between primary human renal tubular cells and endothelial cells in cocultures.

PubMed

Tasnim, Farah; Zink, Daniele

2012-04-15

Interactions between renal tubular epithelial cells and adjacent endothelial cells are essential for normal renal functions but also play important roles in renal disease and repair. Here, we investigated cocultures of human primary renal proximal tubular cells (HPTC) and human primary endothelial cells to address the cross talk between these cell types. HPTC showed improved proliferation, marker gene expression, and enzyme activity in cocultures. Also, the long-term maintenance of epithelia formed by HPTC was improved, which was due to the secretion of transforming growth factor-β1 and its antagonist α2-macroglobulin. HPTC induced endothelial cells to secrete increased amounts of these factors, which balanced each other functionally and only displayed in combination the observed positive effects. In addition, in the presence of HPTC endothelial cells expressed increased amounts of hepatocyte growth factor and vascular endothelial growth factor, which have well-characterized effects on renal tubular epithelial cells as well as on endothelial cells. Together, the results showed that HPTC stimulated endothelial cells to express a functionally balanced combination of various factors, which in turn improved the performance of HPTC. The results give new insights into the cross talk between renal epithelial and endothelial cells and suggest that cocultures could be also useful models for the analysis of cellular communication in renal disease and repair. Furthermore, the characterization of defined microenvironments, which positively affect HPTC, will be helpful for improving the performance of this cell type in in vitro applications including in vitro toxicology and kidney tissue engineering.

Pink1/Parkin-mediated mitophagy play a protective role in cisplatin induced renal tubular epithelial cells injury.

PubMed

Zhao, Chuanyan; Chen, Zhuyun; Xu, Xueqiang; An, Xiaofei; Duan, Suyan; Huang, Zhimin; Zhang, Chengning; Wu, Lin; Zhang, Bo; Zhang, Aihua; Xing, Changying; Yuan, Yanggang

2017-01-15

Cisplatin often causes acute kidney injury (AKI) in the treatment of a wide variety of malignancies. Mitochondrial dysfunction is one of the main reasons for cisplatin nephrotoxicity. Previous study showed that Pink1 and Parkin play central roles in regulating the mitophagy, which is a key protective mechanism by specifically eliminating dysfunctional or damaged mitochondria. However, the mechanisms that modulate mitophagy in cisplatin induced nephrotoxicity remain to be elucidated. The purpose of this study was to investigate the effects of Pink1/Parkin pathway in mitophagy, mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. In cultured human renal proximal tubular cells, we found that knockdown of Pink1/Parkin induced the aggravation of mitochondrial function, leading to the increase of cell injury through inhibition of mitophagy. Additionally, the overexpression of Pink1/Parkin protected against cisplatin-induced mitochondrial dysfunction and cell injury by promoting mitophagy. Our results provide clear evidence that Pink1/Parkin-dependent mitophagy has identified potential targets for the treatment of cisplatin-induced AKI. Copyright © 2016 Elsevier Inc. All rights reserved.

Ischemic acute renal failure and antioxidant therapy in the rat. The relation between glomerular and tubular dysfunction.

PubMed Central

Bird, J E; Milhoan, K; Wilson, C B; Young, S G; Mundy, C A; Parthasarathy, S; Blantz, R C

1988-01-01

The effects of antioxidant therapy with probucol were evaluated in rats subjected to 1 h renal ischemia and to 24 h reperfusion. Probucol exerted significant antioxidant effects in renal cortical tubules in vitro when exposed to a catalase-resistant oxidant. At 24 h probucol treatment (IP) improved single nephron glomerular filtration rate (SNGFR) (28.1 +/- 3.3 nl/min) in comparison to untreated ischemic (I) rats (15.2 +/- 3.0), primarily as a result of improving SNGFR in a population of low SNGFR, low flow and/or obstructed nephrons. However, absolute proximal reabsorption remained abnormally low in IP rats at 24 h (5.9 +/- 0.8 nl/min), and cell necrosis was greater than in I rats. Kidney GFR remained low in IP rats due to extensive tubular backleak of inulin measured by microinjection studies. Evaluations after 2 h of reperfusion revealed a higher SNGFR in IP (36 +/- 3.1 nl/min) than I rats (20.8 +/- 2.7 nl/min). Absolute proximal reabsorption was essentially normal (11.6 +/- 1.3 nl/min) in IP rats, which was higher than IP rats at 24 h and the concurrent I rats. Administration of the lipophilic antioxidant, probucol, increased SNGFR and proximal tubular reabsorption within 2 h after ischemic renal failure. Although SNGFR remained higher than I rats at 24 h, absolute reabsorption fell below normal levels and tubular necrosis was more extensive in IP rats. Early improvement in nephron filtration with antioxidants may increase load dependent metabolic demand upon tubules and increase the extent of damage and transport dysfunction. Images PMID:2835399

S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy.

PubMed

Tammaro, Alessandra; Florquin, Sandrine; Brok, Mascha; Claessen, Nike; Butter, Loes M; Teske, Gwendoline J D; de Boer, Onno J; Vogl, Thomas; Leemans, Jaklien C; Dessing, Mark C

2018-05-10

Despite advances in our understanding of the mechanisms underlying progression of chronic kidney disease and the development of fibrosis, only limited efficacious therapies exist. The calcium binding protein S100A8/A9, is a damage-associated molecular pattern which can activate TLR4 or RAGE. Activation of these receptors is involved in the progression of renal fibrosis, however the role of S100A8/A9 herein remains unknown. Therefore, we analyzed S100A8/A9 expression in patients and mice with obstructive nephropathy and subjected wild-type and S100A9 KO mice lacking the heterodimer S100A8/A9 to Unilateral Ureteral Obstruction (UUO). We found profound S100A8/A9 expression in granulocytes that infiltrated human and murine kidney, together with enhanced renal expression over time, following UUO. S100A9 KO mice were protected from UUO-induced renal fibrosis, independently of leukocyte infiltration and inflammation. Loss of S100A8/A9 protected tubular epithelial cells from UUO-induced apoptosis and critical epithelial-mesenchymal transition steps. In vitro studies revealed S100A8/A9 as a novel mediator of epithelial cell injury, through loss of cell polarity, cell cycle arrest and subsequent cell death. In conclusion, we demonstrate that S100A8/A9 mediates renal damage and fibrosis presumably through loss of tubular epithelial cell contacts and irreversible damage. Suppression of S100A8/A9 could be a therapeutic strategy to halt renal fibrosis in patients with chronic kidney disease. This article is protected by copyright. All rights reserved. © 2018 British Society for Immunology.

Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes

PubMed Central

Yun, Bo; Azad, Mohammad A. K.; Nowell, Cameron J.; Nation, Roger L.; Thompson, Philip E.; Roberts, Kade D.

2015-01-01

Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity. PMID:26392495

Vasopressin Mediates the Renal Damage Induced by Limited Fructose Rehydration in Recurrently Dehydrated Rats.

PubMed

García-Arroyo, Fernando E; Tapia, Edilia; Blas-Marron, Mónica G; Gonzaga, Guillermo; Silverio, Octaviano; Cristóbal, Magdalena; Osorio, Horacio; Arellano-Buendía, Abraham S; Zazueta, Cecilia; Aparicio-Trejo, Omar Emiliano; Reyes-García, Juan G; Pedraza-Chaverri, José; Soto, Virgilia; Roncal-Jiménez, Carlos; Johnson, Richard J; Sánchez-Lozada, Laura G

2017-01-01

Recurrent dehydration and heat stress cause chronic kidney damage in experimental animals. The injury is exacerbated by rehydration with fructose-containing beverages. Fructose may amplify dehydration-induced injury by directly stimulating vasopressin release and also by acting as a substrate for the aldose reductase-fructokinase pathway, as both of these systems are active during dehydration. The role of vasopressin in heat stress associated injury has not to date been explored. Here we show that the amplification of renal damage mediated by fructose in thermal dehydration is mediated by vasopressin. Fructose rehydration markedly enhanced vasopressin (copeptin) levels and activation of the aldose reductase-fructokinase pathway in the kidney. Moreover, the amplification of the renal functional changes (decreased creatinine clearance and tubular injury with systemic inflammation, renal oxidative stress, and mitochondrial dysfunction) were prevented by the blockade of V1a and V2 vasopressin receptors with conivaptan. On the other hand, there are also other operative mechanisms when water is used as rehydration fluid that produce milder renal damage that is not fully corrected by vasopressin blockade. Therefore, we clearly showed evidence of the cross-talk between fructose, even at small doses, and vasopressin that interact to amplify the renal damage induced by dehydration. These data may be relevant for heat stress nephropathy as well as for other renal pathologies due to the current generalized consumption of fructose and deficient hydration habits.

Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria.

PubMed

Wong, Dickson W L; Yiu, Wai Han; Chan, Kam Wa; Li, Ye; Li, Bin; Lok, Sarah W Y; Taketo, Makoto M; Igarashi, Peter; Chan, Loretta Y Y; Leung, Joseph C K; Lai, Kar Neng; Tang, Sydney C W

2018-06-01

Imbalance of Wnt/β-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/β-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/β-catenin, we generated a novel transgenic "Tubcat" mouse conditionally expressing stabilized β-catenin specifically in renal tubules following tamoxifen administration. Four weeks after tamoxifen injection, uninephrectomized Tubcat mice displayed proteinuria and elevated blood urea nitrogen levels compared to non-transgenic mice, implying a detrimental effect of the activated signaling. This was associated with infiltration of the tubulointerstitium predominantly by M1 macrophages and overexpression of the inflammatory chemocytokines CCL-2 and RANTES. Induction of overload proteinuria by intraperitoneal injection of low-endotoxin bovine serum albumin following uninephrectomy for four weeks aggravated proteinuria and increased blood urea nitrogen levels to a significantly greater extent in Tubcat mice. Renal dysfunction correlated with the degree of M1 macrophage infiltration in the tubulointerstitium and renal cortical up-regulation of CCL-2, IL-17A, IL-1β, CXCL1, and ICAM-1. There was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, independent of bovine serum albumin injection. Finally, there was no fibrosis, activation of epithelial-mesenchymal transition or non-canonical Wnt pathways observed in the kidneys of Tubcat mice. Thus, conditional activation of renal tubular Wnt/β-catenin signaling in a novel transgenic mouse model demonstrates that this pathway enhances intrarenal inflammation via the TLR-4/NLRP-3 inflammasome axis in overload proteinuria. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Neural regulation of renal tubular sodium reabsorption and renin secretion: integrative aspects.

PubMed

DiBona, G F

1987-01-01

Efferent renal sympathetic nerve activity plays an important role in the regulation of renal function. Via its direct influence on renal tubular sodium reabsorption throughout the entire mammalian nephron, alterations in efferent renal sympathetic nerve activity represent an important physiological contribution to the overall role of the kidney in the regulation of external sodium balance and the defense against sodium deficit and surfeit. Abnormalities of this mechanism can lead to inappropriate renal sodium retention and augmentation of renin secretion, two factors which are capable of contributing to the development and maintenance of hypertension.

Interferon-γ Reduces the Proliferation of Primed Human Renal Tubular Cells

PubMed Central

García-Sánchez, Omar; López-Novoa, José Miguel; López-Hernández, Francisco J.

2014-01-01

Background/Aims Chronic kidney disease (CKD) is a progressive deterioration of the kidney function, which may eventually lead to renal failure and the need for dialysis or kidney transplant. Whether initiated in the glomeruli or the tubuli, CKD is characterized by progressive nephron loss, for which the process of tubular deletion is of key importance. Tubular deletion results from tubular epithelial cell death and defective repair, leading to scarring of the renal parenchyma. Several cytokines and signaling pathways, including transforming growth factor-β (TGF-β) and the Fas pathway, have been shown to participate in vivo in tubular cell death. However, there is some controversy about their mode of action, since a direct effect on normal tubular cells has not been demonstrated. We hypothesized that epithelial cells would require specific priming to become sensitive to TGF-β or Fas stimulation and that this priming would be brought about by specific mediators found in the pathological scenario. Methods Herein we studied whether the combined effect of several stimuli known to take part in CKD progression, namely TGF-β, tumor necrosis factor-α, interferon-γ (IFN-γ), and Fas stimulation, on primed resistant human tubular cells caused cell death or reduced proliferation. Results We demonstrate that these cytokines have no synergistic effect on the proliferation or viability of human kidney (HK2) cells. We also demonstrate that IFN-γ, but not the other stimuli, reduces the proliferation of cycloheximide-primed HK2 cells without affecting their viability. Conclusion Our results point at a potentially important role of IFN-γ in defective repair, leading to nephron loss during CKD. PMID:24575118

Expression of cleaved caspase-3 in renal tubular cells in Plasmodium falciparum malaria patients.

PubMed

Wichapoon, Benjamas; Punsawad, Chuchard; Viriyavejakul, Parnpen

2017-01-01

In Plasmodium falciparum malaria, the clinical manifestation of acute kidney injury (AKI) is commonly associated with acute tubular necrosis (ATN) in the kidney tissues. Renal tubular cells often exhibit various degrees of cloudy swelling, cell degeneration, and frank necrosis. To study individual cell death, this study evaluates the degree of renal tubular necrosis in association with apoptosis in malarial kidneys. Kidney tissues from P. falciparum malaria with AKI (10 cases), and without AKI (10 cases) were evaluated for tubular pathology. Normal kidney tissues from 10 cases served as controls. Tubular necrosis was assessed quantitatively in kidney tissues infected with P. falciparum malaria, based on histopathological evaluation. In addition, the occurrence of apoptosis was investigated using cleaved caspase-3 marker. Correlation between tubular necrosis and apoptosis was analyzed. Tubular necrosis was found to be highest in P. falciparum malaria patients with AKI (36.44% ± 3.21), compared to non-AKI (15.88% ± 1.63) and control groups (2.58% ± 0.39) (all p < 0.001). In the AKI group, the distal tubules showed a significantly higher degree of tubular necrosis than the proximal tubules (p = 0.021) and collecting tubules (p = 0.033). Tubular necrosis was significantly correlated with the level of serum creatinine (r = 0.596, p = 0.006), and the occurrence of apoptosis (r = 0.681, p = 0.001). In malarial AKI, the process of apoptosis occurs in ATN. © 2016 Asian Pacific Society of Nephrology.

Hypertension and Hyperglycemia Synergize to Cause Incipient Renal Tubular Alterations Resulting in Increased NGAL Urinary Excretion in Rats

PubMed Central

Blázquez-Medela, Ana M.; García-Sánchez, Omar; Blanco-Gozalo, Víctor; Quiros, Yaremi; Montero, María J.; Martínez-Salgado, Carlos; López-Novoa, José M.; López-Hernández, Francisco J.

2014-01-01

Background Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. Methods Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). Results Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. Conclusions Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion. PMID:25148248

Hypertension and hyperglycemia synergize to cause incipient renal tubular alterations resulting in increased NGAL urinary excretion in rats.

PubMed

Blázquez-Medela, Ana M; García-Sánchez, Omar; Blanco-Gozalo, Víctor; Quiros, Yaremi; Montero, María J; Martínez-Salgado, Carlos; López-Novoa, José M; López-Hernández, Francisco J

2014-01-01

Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion.

Transient renal tubulopathy in a racing Greyhound.

PubMed

Abraham, L A; Tyrrell, D; Charles, J A

2006-11-01

A 2-year-old female Greyhound was presented for inappetence and lethargy. On referral, results of diagnostic tests indicated renal glucosuria, increased excretion of selected amino acids and abnormal fractional excretion of electrolytes consistent with renal tubular dysfunction. Systemic blood pressure was elevated. Renal biopsy revealed mild proximal renal tubular damage consistent with a subacute toxic or hypoxic insult. Systemic hypertension, renal glucosuria and altered fractional excretion of electrolytes resolved during the 7 day period of hospital treatment. The Greyhound resumed training without recurrence of renal dysfunction.

Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes.

PubMed

Yun, Bo; Azad, Mohammad A K; Nowell, Cameron J; Nation, Roger L; Thompson, Philip E; Roberts, Kade D; Velkov, Tony; Li, Jian

2015-12-01

Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells.

PubMed

Zhang, Wei; Zhou, Xiangjun; Yao, Qisheng; Liu, Yutao; Zhang, Hao; Dong, Zheng

2017-10-01

Exosomes are nano-sized vesicles produced and secreted by cells to mediate intercellular communication. The production and function of exosomes in kidney tissues and cells remain largely unclear. Hypoxia is a common pathophysiological condition in kidneys. This study was designed to characterize exosome production during hypoxia of rat renal proximal tubular cells (RPTCs), investigate the regulation by hypoxia-inducible factor-1 (HIF-1), and determine the effect of the exosomes on ATP-depletion-induced tubular cell injury. Hypoxia did not change the average sizes of exosomes secreted by RPTCs, but it significantly increased exosome production in a time-dependent manner. HIF-1 induction with dimethyloxalylglycine also promoted exosome secretion, whereas pharmacological and genetic suppression of HIF-1 abrogated the increase of exosome secretion under hypoxia. The exosomes from hypoxic RPTCs had inhibitory effects on apoptosis of RPTCs following ATP depletion. The protective effects were lost in the exosomes from HIF-1α knockdown cells. It is concluded that hypoxia stimulates exosome production and secretion in renal tubular cells. The exosomes from hypoxic cells are protective against renal tubular cell injury. HIF-1 mediates exosome production during hypoxia and contributes to the cytoprotective effect of the exosomes. Copyright © 2017 the American Physiological Society.

Renal tubular-cell neoplasms in black-footed ferrets (Mustela nigripes)--38 cases.

PubMed

Lair, S; Barker, I K; Mehren, K G; Williams, E S

2006-05-01

Thirty-eight cases of renal tubular cell neoplasms were diagnosed in 184 captive, adult (>1-year-old), black-footed ferrets (Mustela nigripes) examined from 1985 to 1996. This prevalence (20.7%) is one of the highest reported for this neoplasm in a population of animals. These tumors rarely metastasized (1/38), and usually were incidental postmortem findings, associated clinical disease being present in only 3 (8%) of the 38 cases. The prevalence of renal tubular cell neoplasms found at postmortem examination increased linearly with age, up to 67% in ferrets >8 years old. Both males (prevalence = 19%) and females (prevalence = 24%) were affected. Multiple renal tumors were common, and seven ferrets (18.4% of affected animals) had bilateral tumors. The cause of this neoplastic syndrome could not be determined. Since most of the animals affected by this condition were in their postreproductive years of life, the impact of this neoplastic syndrome on the captive propagation of this species is negligible.

Tauroursodeoxycholic Acid Attenuates Renal Tubular Injury in a Mouse Model of Type 2 Diabetes

PubMed Central

Zhang, Jing; Fan, Ying; Zeng, Chuchu; He, Li; Wang, Niansong

2016-01-01

Renal tubular injury is a critical factor in the pathogenesis of diabetic nephropathy (DN). Endoplasmic reticulum (ER) stress is involved in diabetic nephropathy. Tauroursodeoxycholic acid (TUDCA) is an effective inhibitor of ER stress. Here, we investigated the role of TUDCA in the progression of tubular injury in DN. For eight weeks, being treated with TUDCA at 250 mg/kg intraperitoneal injection (i.p.) twice a day, diabetic db/db mice had significantly reduced blood glucose, albuminuria and attenuated renal histopathology. These changes were associated with a significant decreased expression of ER stress markers. At the same time, diabetic db/db mice had more TUNEL-positive nuclei in the renal tubule, which were attenuated by TUDCA treatment, along with decreases in ER stress–associated apoptotic markers in the kidneys. In summary, the effect of TUDCA on tubular injury, in part, is associated with inhibition of ER stress in the kidneys of diabetic db/db mice. TUDCA shows potential as a therapeutic target for the prevention and treatment of DN. PMID:27669287

Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells.

PubMed

Mitsuoka, Keisuke; Shirasaka, Yoshiyuki; Fukushi, Akimasa; Sato, Masanobu; Nakamura, Toshimichi; Nakanishi, Takeo; Tamai, Ikumi

2009-04-01

L-Citrulline has diagnostic potential for renal function, because its plasma concentration increases with the progression of renal failure. Although L-citrulline extracted by glomerular filtration in kidney is mostly reabsorbed, the mechanism involved is not clearly understood. The present study was designed to characterize L-citrulline transport across the apical membranes of renal epithelial tubular cells, using primary-cultured rat renal proximal tubular cells, as well as the human kidney proximal tubular cell line HK-2. L-Citrulline was transported in a Na(+)-dependent manner from the apical side of both cell types cultured on permeable supports with a microporous membrane. Kinetic analysis indicated that the transport involves two distinct Na(+)-dependent saturable systems and one Na(+)-independent saturable system in HK-2 cells. The uptake was competitively inhibited by neutral and cationic, but not anionic amino acids. Relatively large cationic and anionic compounds inhibited the uptake, but smaller ones did not. In HK-2 cells, mRNA expression of SLC6A19 and SLC7A9, which encode B(0)AT1 and b(0,+)AT, respectively, was detected by RT-PCR. In addition, L-citrulline transport was significantly decreased in HK-2 cells in which either SLC6A19 or SLC7A9 was silenced. Hence, these results suggest that amino acid transporters B(0)AT1 and b(0,+)AT are involved in the reabsorption of L-citrulline in the kidney, at least in part, by mediating the apical membrane transport of L-citrulline in renal tubule cells.

The Mitochondria-Targeted Antioxidant Mitoquinone Protects against Cold Storage Injury of Renal Tubular Cells and Rat Kidneys

PubMed Central

Mitchell, Tanecia; Rotaru, Dumitru; Saba, Hamida; Smith, Robin A. J.; Murphy, Michael P.

2011-01-01

The majority of kidneys used for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage before transplantation to preserve tissue quality and allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction after transplantation. We have previously determined mitochondrial superoxide and other downstream oxidants to be important signaling molecules that contribute to CS plus rewarming (RW) injury of rat renal proximal tubular cells. Thus, this study's purpose was to determine whether adding mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to University of Wisconsin (UW) preservation solution could offer protection against CS injury. CS was initiated by placing renal cells or isolated rat kidneys in UW solution alone (4 h at 4°C) or UW solution containing MitoQ or its control compound, decyltriphenylphosphonium bromide (DecylTPP) (1 μM in vitro; 100 μM ex vivo). Oxidant production, mitochondrial function, cell viability, and alterations in renal morphology were assessed after CS exposure. CS induced a 2- to 3-fold increase in mitochondrial superoxide generation and tyrosine nitration, partial inactivation of mitochondrial complexes, and a significant increase in cell death and/or renal damage. MitoQ treatment decreased oxidant production ∼2-fold, completely prevented mitochondrial dysfunction, and significantly improved cell viability and/or renal morphology, whereas DecylTPP treatment did not offer any protection. These findings implicate that MitoQ could potentially be of therapeutic use for reducing organ preservation damage and kidney discardment and/or possibly improving renal function after transplantation. PMID:21159749

The mitochondria-targeted antioxidant mitoquinone protects against cold storage injury of renal tubular cells and rat kidneys.

PubMed

Mitchell, Tanecia; Rotaru, Dumitru; Saba, Hamida; Smith, Robin A J; Murphy, Michael P; MacMillan-Crow, Lee Ann

2011-03-01

The majority of kidneys used for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage before transplantation to preserve tissue quality and allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction after transplantation. We have previously determined mitochondrial superoxide and other downstream oxidants to be important signaling molecules that contribute to CS plus rewarming (RW) injury of rat renal proximal tubular cells. Thus, this study's purpose was to determine whether adding mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to University of Wisconsin (UW) preservation solution could offer protection against CS injury. CS was initiated by placing renal cells or isolated rat kidneys in UW solution alone (4 h at 4°C) or UW solution containing MitoQ or its control compound, decyltriphenylphosphonium bromide (DecylTPP) (1 μM in vitro; 100 μM ex vivo). Oxidant production, mitochondrial function, cell viability, and alterations in renal morphology were assessed after CS exposure. CS induced a 2- to 3-fold increase in mitochondrial superoxide generation and tyrosine nitration, partial inactivation of mitochondrial complexes, and a significant increase in cell death and/or renal damage. MitoQ treatment decreased oxidant production ~2-fold, completely prevented mitochondrial dysfunction, and significantly improved cell viability and/or renal morphology, whereas DecylTPP treatment did not offer any protection. These findings implicate that MitoQ could potentially be of therapeutic use for reducing organ preservation damage and kidney discardment and/or possibly improving renal function after transplantation.

Role of serotonin in the regulation of renal proximal tubular epithelial cells.

PubMed

Erikci, Acelya; Ucar, Gulberk; Yabanoglu-Ciftci, Samiye

2016-08-01

In various renal injuries, tissue damage occurs and platelet activation is observed. Recent studies suggest that some factors, such as serotonin, are released into microenvironment upon platelet activation following renal injury. In the present study, we aimed to investigate whether platelets and platelet-released serotonin are involved in the functional regulation of renal proximal tubular epithelial cells (PTECs). PTECs were obtained by primary cell culture and treated with platelet lysate (PL) (2 × 10(6)/mL, 4 × 10(6)/mL, 8 × 10(6)/mL) or serotonin (1 μM or 5 μM) for 12 or 24 h. Phenotypic transdifferentiation of epithelial cells into myofibroblasts were demonstrated under light microscope and confirmed by the determination of α-smooth muscle actin gene expression. Serotonin and PL were shown to induce epithelial-mesenchymal transdifferentiation of PTECs. After stimulation of PTECs with serotonin or PL, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and collagen-α1 gene expressions, which were reported to be elevated in renal injury, were determined by real-time PCR and found to be upregulated. Expressions of some inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and transforming growth factor-β1 were found to be increased in both protein and gene levels. Recently there is no published report on the effect of serotonin on renal PTECs. Results obtained in this study have lightened the role of serotonin and platelet-mediated effects of serotonin on fibrotic and inflammatory processes in PTECs.

Acquired resistance to rechallenge injury in rats recovered from subclinical renal damage with uranyl acetate-Importance of proliferative activity of tubular cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Yuan; Fujigaki, Yoshihide, E-mail: yf0516@hama-med.ac.j; Sakakima, Masanori

Animals recovered from acute renal failure are resistant to subsequent insult. We investigated whether rats recovered from mild proximal tubule (PT) injury without renal dysfunction (subclinical renal damage) acquire the same resistance. Rats 14 days after recovering from subclinical renal damage, which was induced by 0.2 mg/kg of uranyl acetate (UA) (sub-toxic dose), were rechallenged with 4 mg/kg of UA (nephrotoxic dose). Fate of PT cells and renal function were examined in response to nephrotoxic dose of UA. All divided cells after sub-toxic dose of UA insult were labeled with bromodeoxyuridine (BrdU) for 14 days then the number of PTmore » cells with or without BrdU-labeling was counted following nephrotoxic dose of UA insult. Rats recovered from subclinical renal damage gained resistance to nephrotoxic dose of UA with reduced renal dysfunction, less severity of peak damage (necrotic and TUNEL+ apoptotic cells) and accelerated PT cell proliferation, but with earlier peak of PT damage. The decrease in number of PT cells in the early phase of rechallenge injury with nephrotoxic UA was more in rats pretreated with sub-toxic dose of UA than vehicle pretreated rats. The exaggerated loss of PT cells was mainly caused by the exaggerated loss of BrdU+ divided cells. In contrast, accelerated cell proliferation in rats recovered from sub-toxic dose of UA was observed mainly in BrdU- non-divided cells. The findings suggest that rats recovered from subclinical renal damage showed partial acquired resistance to nephrotoxic insult. Accelerated recovery with increased proliferative activity of non-divided PT cells after subclinical renal damage may mainly contribute to acquired resistance.« less

Curcumin suppresses AGEs induced apoptosis in tubular epithelial cells via protective autophagy

PubMed Central

Wei, Ying; Gao, Jiaqi; Qin, Lingling; Xu, Yunling; Shi, Haoxia; Qu, Lingxia; Liu, Yongqiao; Xu, Tunhai; Liu, Tonghua

2017-01-01

Renal tubular cell apoptosis and tubular dysfunction is an important process underlying diabetic nephropathy (DN). Understanding the mechanisms underlying renal tubular epithelial cell survival is important for the prevention of kidney damage associated with glucotoxicity. Curcumin has been demonstrated to possess potent anti-apoptotic properties. However, the roles of curcumin in renal epithelial cells are yet to be defined. The present study investigated advanced glycation or glycoxidation end-product (AGE)-induced toxicity in renal tubular epithelial cells via several complementary assays, including cell viability, cell apoptosis and cell autophagy in the NRK-52E rat kidney tubular epithelial cell line. The extent of apoptosis was significantly increased in the NRK-52E cells following treatment with AGEs. The results also indicated that curcumin reversed this effect by promoting autophagy through the phosphoinositide 3-kinase/AKT serine/threonine kinase signaling pathway. These conclusions suggested that curcumin exerts a renoprotective effect in the presence of AGEs, at least in part by activating autophagy in NRK-52E cells. Collectively, these findings indicate that curcumin not only exerts renoprotective effects, however may also act as a novel therapeutic strategy for the treatment of diabetic nephropathy. PMID:29285156

IgA-kappa type multiple myeloma affecting proximal and distal renal tubules.

PubMed

Minemura, K; Ichikawa, K; Itoh, N; Suzuki, N; Hara, M; Shigematsu, S; Kobayashi, H; Hiramatsu, K; Hashizume, K

2001-09-01

A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgA kappa multiple myeloma excreting urinary Bence Jones protein (kappa-light chain). Renal biopsy revealed thick basement membranes and elec-tron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappa-light chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age.

Stem Cell Conditioned Culture Media Attenuated Albumin-Induced Epithelial– Mesenchymal Transition in Renal Tubular Cells

PubMed Central

Hu, Junping; Zhu, Qing; Li, Pin-Lan; Wang, Weili; Yi, Fan; Li, Ningjun

2015-01-01

Background Proteinuria-induced epithelial-mesenchymal transition (EMT) plays an important role in progressive renal tubulointerstitial fibrosis in chronic renal disease. Stem cell therapy has been used for different diseases. Stem cell conditioned culture media (SCM) exhibits similar beneficial effects as stem cell therapy. The present study tested the hypothesis that SCM inhibits albumin-induced EMT in cultured renal tubular cells. Methods Rat renal tubular cells were treated with/without albumin (20 μmg/ml) plus SCM or control cell media (CCM). EMT markers and inflammatory factors were measured by Western blot and fluorescent images. Results Albumin induced EMT as shown by significant decreases in levels of epithelial marker E-cadherin, increases in mesenchymal markers fibroblast-specific protein 1 and α-smooth muscle actin, and elevations in collagen I. SCM inhibited all these changes. Meanwhile, albumin induced NF-κB translocation from cytosol into nucleus and that SCM blocked the nuclear translocation of NF-κB. Albumin also increased the levels of pro-inflammatory factor monocyte chemoattractant protein-1 (MCP)-1 by nearly 30 fold compared with control. SCM almost abolished albumin-induced increase of MCP-1. Conclusion These results suggest that SCM attenuated albumin-induced EMT in renal tubular cells via inhibiting activation of inflammatory factors, which may serve as a new therapeutic approach for chronic kidney diseases. PMID:25832005

Renal tubular disease in the era of combination antiretroviral therapy.

PubMed

Hamzah, Lisa; Booth, John W; Jose, Sophie; McAdoo, Stephen P; Kumar, Emil A; O'Donnell, Patrick; Hilton, Rachel; Sabin, Caroline; Williams, Deborah I; Jones, Rachael; Post, Frank A

2015-09-10

To describe the spectrum of renal tubular disease (RTD) in HIV-positive patients and its association with exposure to antiretroviral therapy (ART). Review of 265 consecutive renal biopsies from HIV-positive patients attending eight clinics in the United Kingdom between 2000 and 2012. We described the clinical characteristics of patients with RTD and compared current/recent exposure (at the time of, or up to 3 months prior to the date of biopsy) to potentially nephrotoxic ART [tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir/ritonavir (LPV/r)]. We also analysed the incidence of RTD in the UK CHIC cohort. Kruskall-Wallis, analysis of variance and Fisher's exact tests were used to evaluate between-group differences. Of the 60 RTD cases, 54 (90%) were included in the analyses. RTD comprised of three distinct patterns: acute tubular injury (ATI, n = 22), tubulo-interstitial nephritis (TIN, n = 20) and interstitial fibrosis and tubular atrophy (IFTA, n = 12). Compared with TIN and IFTA, ATI cases were less likely to be of black ethnicity (10 vs. 42-55%; P = 0.006), more likely to be on ART (100 vs. 55-68%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54-58%; P < 0.001), and more likely to have current/recent exposure to TDF (P < 0.001). We did not find evidence for an association between exposure to TDF, ATV/r or LPV/r and either TIN or IFTA. RTD was present in approximately 20% of renal biopsies and comprised three distinct injury patterns with considerable clinical overlap. ATI was associated with TDF exposure, although the overall incidence of biopsy-defined ATI was low.

Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis

PubMed Central

Simon, Noémie; Hertig, Alexandre

2015-01-01

Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research. PMID:26301223

Smart concrete slabs with embedded tubular PZT transducers for damage detection

NASA Astrophysics Data System (ADS)

Gao, Weihang; Huo, Linsheng; Li, Hongnan; Song, Gangbing

2018-02-01

The objective of this study is to develop a new concept and methodology of smart concrete slab (SCS) with embedded tubular lead zirconate titanate transducer array for image based damage detection. Stress waves, as the detecting signals, are generated by the embedded tubular piezoceramic transducers in the SCS. Tubular piezoceramic transducers are used due to their capacity of generating radially uniform stress waves in a two-dimensional concrete slab (such as bridge decks and walls), increasing the monitoring range. A circular type delay-and-sum (DAS) imaging algorithm is developed to image the active acoustic sources based on the direct response received by each sensor. After the scattering signals from the damage are obtained by subtracting the baseline response of the concrete structures from those of the defective ones, the elliptical type DAS imaging algorithm is employed to process the scattering signals and reconstruct the image of the damage. Finally, two experiments, including active acoustic source monitoring and damage imaging for concrete structures, are carried out to illustrate and demonstrate the effectiveness of the proposed method.

Protective effect of 20-hydroxyeicosatetraenoic acid (20-HETE) on adriamycin-induced toxicity of human renal tubular epithelial cell (HK-2).

PubMed

Tian, Ting; Li, Jin; Wang, Meng-Ying; Xie, Xian-Fei; Li, Qi-Xiong

2012-05-15

20-Hydroxyeicosatetraenoic acid is a cytochrome P4504A11 metabolite of arachidonic acid that plays an important role in the regulation of human renal functions. In the present study, we investigated the role of 20-hydroxyeicosatetraenoic acid on adriamycin induced toxicity in human renal tubular epithelial cells. Results showed that cell viability was decreased significantly and lactate dehydrogenase activity was increased significantly in a concentration-dependent manner when human renal tubular epithelial cells were incubated with adriamycin (10⁻⁷-10⁻³ mol/l) for 24h. In contrast, 20-hydroxyeicosatetraenoic acid (0.1, 1, 10, 50 μmol/l) increased cell survival and decreased lactate dehydrogenase activity concentration dependently in human renal tubular epithelial cells. When 20-hydroxyeicosatetraenoic acid (10, 50 μmol/l) was co-administered with adriamycin (10⁻³ mol/l), it significantly increased cell viability and decreased lactate dehydrogenase activity. On the other hand, N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET-0016) (1 μM), a selective inhibitor of 20-hydroxyeicosatetraenoic acid synthesizing enzyme exaggerated cell viability reduction and lactate dehydrogenase activity augmentation induced by adriamycin. Adriamycin suppressed the expression of cytochrome P4504A11 gene and its protein production in human renal tubular epithelial cells. Furthermore, adriamycin was more effective than N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine at lowering the expression of cytochrome P4504A11 gene and its protein. These results suggest that 20-hydroxyeicosatetraenoic acid may protect adriamycin-induced toxicity of human renal tubular epithelial cells, meanwhile, adriamycin-induced toxicity of human renal tubular epithelial cells possibly involves inhibiting cytochrome P4504A11 expression. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Comprehensive clinical approach to renal tubular acidosis.

PubMed

Sharma, Sonia; Gupta, Ankur; Saxena, Sanjiv

2015-08-01

Renal tubular acidosis (RTA) is essentially characterized by normal anion gap and hyperchloremic metabolic acidosis. It is important to understand that despite knowing the disease for 60-70 years, complexities in the laboratory tests and their interpretation still make clinicians cautious to diagnose and label types of tubular disorder. Hence, we are writing this mini-review to emphasize on the step wise approach to RTA with some understanding on its basic etiopathogenesis. This will definitely help to have an accurate interpretation of urine and blood reports in correlation with the clinical condition. RTA can be a primary or secondary defect and results either due to abnormality in bicarbonate ion absorption or hydrogen ion secretion. Primary defects are common in children due to gene mutation or idiopathic nature while secondary forms are more common in adults. We are focusing and explaining here in this review all the clinical and laboratory parameters which are essential for making the diagnosis of RTA and excluding the extrarenal causes of hyperchloremic, normal anion gap metabolic acidosis.

Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis.

PubMed

Taniai, Eriko; Hayashi, Hitomi; Yafune, Atsunori; Watanabe, Maiko; Akane, Hirotoshi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2012-09-01

Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα-immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G₂. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G₂/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G₂ arrest in the target tubular cells.

Poly[ADP-ribose] polymerase-1 expression is related to cold ischemia, acute tubular necrosis, and delayed renal function in kidney transplantation.

PubMed

O'Valle, Francisco; Del Moral, Raimundo G M; Benítez, María del Carmén; Martín-Oliva, David; Gómez-Morales, Mercedes; Aguilar, David; Aneiros-Fernández, José; Hernández-Cortés, Pedro; Osuna, Antonio; Moreso, Francesc; Serón, Daniel; Oliver, Francisco J; Del Moral, Raimundo G

2009-09-28

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN). Nuclear PARP-1 immunohistochemical expression was studied in 326 paraffin-embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury. PARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p = 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function.

Role of the glomerular-tubular imbalance with tubular predominance in the arterial hypertension pathophysiology.

PubMed

Fox, María Ofelia Barber; Gutiérrez, Ernesto Barber

2013-09-01

In previous investigations we caused renal tubular reabsorption preponderance relating to the glomerular filtration (Glomerular-tubular imbalance) and we observed that this fact conducted to volume expansion and development of arterial hypertension, in rats that previously were normotens. We based on this evidence and other which are reflected in the literature arrived at the following hypothesis: a greater proportion of tubular reabsorption relating to the filtered volume is the base of the establishment of the glomerular-tubular imbalance with tubular predominance (GTI-T), which favors to the Na(+)-fluid retention and volume expansion. All of which conduced to arterial hypertension. These facts explain a primary hypertensive role of the kidney, consistent with the results of renal transplants performed in different lines of hypertensive rats and their respective controls and in humans: hypertension can be transferred with the kidney. GTI-T aims to be, a common phenomenon involved in the hypertension development in the multiple ways which is manifested the hypertensive syndrome. In secondary hypertension, GTI-T is caused by significant disruptions of hormone secretions that control renal function, or obvious vascular or parenchymal damage of these organs. In primary hypertension the GTI-T has less obvious causes inherently developed in the kidney, including humoral, cellular and subcellular mechanisms, which may insidiously manifest under environmental factors influence, resulting in insidious development of hypertension. This would explain the state of prehypertension that these individuals suffer. So it has great importance to study GTI-T before the hypertension is established, because when hypertensive state is established, other mechanisms are installed and they contribute to maintain the hypertension. Our hypothesis may explaining the inability of the kidneys to excrete salt and water in hypertension, as Guyton and colleagues have expressed and constitutes a

A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells.

PubMed

Guo, Deng-Fu; Tardif, Valerie; Ghelima, Karin; Chan, John S D; Ingelfinger, Julie R; Chen, XiangMei; Chenier, Isabelle

2004-05-14

Angiotensin II stimulates cellular hypertrophy in cultured vascular smooth muscle and renal proximal tubular cells. This effect is believed to be one of earliest morphological changes of heart and renal failure. However, the precise molecular mechanism involved in angiotensin II-induced hypertrophy is poorly understood. In the present study we report the isolation of a novel angiotensin II type 1 receptor-associated protein. It encodes a 531-amino acid protein. Its mRNA is detected in all human tissues examined but highly expressed in the human kidney, pancreas, heart, and human embryonic kidney cells as well as rat vascular smooth muscle and renal proximal tubular cells. Protein synthesis and relative cell size analyzed by flow cytometry studies indicate that overexpression of the novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in cultured rat vascular smooth muscle and renal proximal tubular cells. In contrast, the hypertrophic effects was reversed in renal proximal tubular cell lines expressing the novel gene in the antisense orientation and its dominant negative mutant, which lacks the last 101 amino acids in its carboxyl-terminal tail. The hypertrophic effects are at least in part mediated via protein kinase B activation or cyclin-dependent kinase inhibitor, p27(kip1) protein expression level in vascular smooth muscle, and renal proximal tubular cells. Moreover, angiotensin II could not stimulate cellular hypertrophy in renal proximal tubular cells expressing the novel gene in the antisense orientation and its mutant. These findings may provide new molecular mechanisms to understand hypertrophic agents such as angiotensin II-induced cellular hypertrophy.

Amelioration of renal ischaemia–reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells

PubMed Central

Rogers, NM; Stephenson, MD; Kitching, AR; Horowitz, JD; Coates, PTH

2012-01-01

BACKGROUND AND PURPOSE Renal ischaemia–reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway. EXPERIMENTAL APPROACH We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting. KEY RESULTS Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein. CONCLUSIONS AND IMPLICATIONS Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury. PMID:21745189

Long-term low-dose glucocorticoid therapy associated with remission of overt renal tubular acidosis in Sjögren's syndrome.

PubMed

el-Mallakh, R S; Bryan, R K; Masi, A T; Kelly, C E; Rakowski, K J

1985-10-01

Renal tubular acidosis and focal interstitial inflammatory cell infiltrate secondary to Sjögren's syndrome remitted with low-dose glucocorticoid therapy over five and one half years in a patient with associated mild systemic lupus erythematosus. Such response has not been previously documented. This observation may have therapeutic applications for renal tubular acidosis associated with Sjögren's syndrome that deserve further investigation.

Distal renal tubular dysfunction: a common feature in calcium stone formers.

PubMed

Megevand, M; Favre, H

1984-12-01

Distal renal tubular acidosis has been reported as an uncommon cause of urinary calcium stone disease. However, this defect appears to be more frequent when appropriate tests are performed systematically. Twenty-nine patients with recurrent calcium stones have been separated into three groups: normocalciuric (group A), renal hypercalciuric (group B) and absorptive hypercalciuric (group C). Distal tubular functions were investigated by the (urine-blood) pCO2 gradient and by an ammonium chloride test. (Urine-blood) pCO2 gradient was (mean +/- SEM), 3.33 +/- 0.59 in group A, 2.95 +/- 0.34 in group B and 3.31 +/- 0.58 kPa in group C. All these values differ significantly from those observed in controls (4.11 +/- 0.28 kPa; P less than 0.05). After 3 days of ammonium chloride loading, ammonium excretion averaged 54.7 +/- 4.2 in group A, 54.4 +/- 4.3 in group B and 64.3 +/- 5.5 mumol min-1 in group C. Values obtained in the first two groups were significantly lower than that achieved by control subjects (76.4 +/- 14.9 mumol min-1). It is concluded that tubular dysfunctions defined as impairments in hydrogen ion secretion and ammonium excretion after an acid challenge are a common feature of the urinary calcium stone disease and play a contributory role in its pathogenesis.

Exosome production and its regulation of EGFR during wound healing in renal tubular cells.

PubMed

Zhou, Xiangjun; Zhang, Wei; Yao, Qisheng; Zhang, Hao; Dong, Guie; Zhang, Ming; Liu, Yutao; Chen, Jian-Kang; Dong, Zheng

2017-06-01

Kidney repair following injury involves the reconstitution of a structurally and functionally intact tubular epithelium. Growth factors and their receptors, such as EGFR, are important in the repair of renal tubules. Exosomes are cell-produced small (~100 nm in diameter) vesicles that contain and transfer proteins, lipids, RNAs, and DNAs between cells. In this study, we examined the relationship between exosome production and EGFR activation and the potential role of exosome in wound healing. EGFR activation occurred shortly after scratch wounding in renal tubular cells. Wound repair after scratching was significantly promoted by EGF and suppressed by EGFR inhibitor gefitinib. Interestingly, scratch wounding induced a significant increase of exosome production. The exosome production was decreased by EGF and increased by gefitinib, suggesting a suppressive role of EGFR signaling in exosome production. Conversely, inhibition of exosome release by GW4869 and manumycin A markedly increased EGFR activation and promoted wound healing. Moreover, exosomes derived from scratch-wounding cells could inhibit wound healing. Collectively, the results indicate that wound healing in renal tubular cells is associated with EGFR activation and exosome production. Although EGFR activation promotes wound healing, released exosomes may antagonize EGFR activation and wound healing. Copyright © 2017 the American Physiological Society.

Diffuse Lymphomatous Infiltration of Kidney Presenting as Renal Tubular Acidosis and Hypokalemic Paralysis: Case Report

PubMed Central

Jhamb, Rajat; Gupta, Naresh; Garg, Sandeep; Kumar, Sachin; Gulati, Sameer; Mishra, Deepak; Beniwal, Pankaj

2007-01-01

We report the case of a 22-year-old woman who presented with acute onset flaccid quadriparesis. Physical examination showed mild pallor with cervical and axillary lymphadenopathy, hepatomegaly, and bilateral smooth enlarged kidneys. Neurological examination revealed lower motor neuron muscle weakness in all the four limbs with hyporeflexia and normal sensory examination. Laboratory investigations showed anemia, severe hypokalemia, and metabolic acidosis. Urinalysis showed a specific gravity of 1.010, pH of 7.0, with a positive urine anion gap. Ultrasound revealed hepatosplenomegaly with bilateral enlarged smooth kidneys. Renal biopsy was consistent with the diagnosis of non-Hodgkin lymphoma (B cell type). Metabolic acidosis, alkaline urine, and severe hypokalemia due to excessive urinary loss in our patient were suggestive of distal renal tubular acidosis. Renal involvement in lymphoma is usually subclinical and clinically overt renal disease is rare. Diffuse lymphomatous infiltration of the kidneys may cause tubular dysfunction and present with hypokalemic paralysis. PMID:18074421

Dental Aspect of Distal Tubular Renal Acidosis with Genu Valgum Secondary to Rickets: A Case Report

PubMed Central

Bahadure, Rakesh N.; Thosar, Nilima; Kriplani, Ritika; Baliga, Sudhindra; Fulzele, Punit

2012-01-01

Distal renal tubular acidosis is a disease that occurs when the kidneys do not remove acid properly into the urine, leaving the blood too acidic (called acidosis). Distal renal tubular acidosis (type I RTA) is caused by a defect in the kidney tubes that causes acid to build up in the bloodstream. It ultimately results rickets which include chronic skeletal pain, in skeletal deformities, skeletal fractures. Rickets is among the most frequent childhood diseases in many developing countries. Dental problems in rickets include delayed eruption of permanent teeth, premature fall of deciduous teeth, defects in structure of teeth, enamel defects in permanent teeth (hypoplastic), pulp defects, intraglobular dentine, and caries tooth. Herewith, reported a case of distal tubular renal acidosis with genu valgum secondary to rickets, with pain and extraoral swelling associated with right and left mandibular 1st permanent molars. Teeth were infected with pulp without being involved with caries. Radiographically cracks in enamel and dentin were observed. Pulp revascularization with 46 and root canal treatment was done for 36 with followup of 1 year. PMID:22567455

Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury.

PubMed

Ahmad, Tariq; Jackson, Keyanna; Rao, Veena S; Tang, W H Wilson; Brisco-Bacik, Meredith A; Chen, Horng H; Felker, G Michael; Hernandez, Adrian F; O'Connor, Christopher M; Sabbisetti, Venkata S; Bonventre, Joseph V; Wilson, F Perry; Coca, Steven G; Testani, Jeffrey M

2018-05-08

Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N -acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N -acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P >0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P <0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin ( P =0.21), N -acetyl-β-d-glucosaminidase ( P =0.46), or kidney injury molecule 1 ( P =0.22). Increases in neutrophil gelatinase-associated lipocalin, N -acetyl

Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells.

PubMed

Rogers, N M; Stephenson, M D; Kitching, A R; Horowitz, J D; Coates, P T H

2012-05-01

Renal ischaemia-reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway. We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting. Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein. Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

The urinary excretion of metformin, ceftizoxime and ofloxacin in high serum creatinine rats: Can creatinine predict renal tubular elimination?

PubMed

Ma, Yan-Rong; Zhou, Yan; Huang, Jing; Qin, Hong-Yan; Wang, Pei; Wu, Xin-An

2018-03-01

The renal excretion of creatinine and most drugs are the net result of glomerular filtration and tubular secretion, and their tubular secretions are mediated by individual transporters. Thus, we hypothesized that the increase of serum creatinine (SCr) levels attributing to inhibiting tubular transporters but not glomerular filtration rate (GFR) could be used to evaluate the tubular excretion of drugs mediated by identical or partial overlap transporter with creatinine. In this work, we firstly developed the creatinine excretion inhibition model with normal GFR by competitively inhibiting tubular transporters, and investigated the renal excretion of metformin, ceftizoxime and ofloxacin in vivo and in vitro. The results showed that the 24-hour urinary excretion of metformin and ceftizoxime in model rats were decreased by 25% and 17% compared to that in control rats, respectively. The uptake amount and urinary excretion of metformin and ceftizoxime could be inhibited by creatinine in renal cortical slices and isolated kidney perfusion. However, the urinary excretion of ofloxacin was not affected by high SCr. These results showed that the inhibition of tubular creatinine transporters by high SCr resulted to the decrease of urinary excretion of metformin and ceftizoxime, but not ofloxacin, which implied that the increase of SCr could also be used to evaluate the tubular excretion of drugs mediated by identical or partial overlap transporter with creatinine in normal GFR rats. Copyright © 2018 Elsevier Inc. All rights reserved.

Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

PubMed Central

O'Valle, Francisco; Del Moral, Raimundo G. M.; Benítez, María del Carmén; Martín-Oliva, David; Gómez-Morales, Mercedes; Aguilar, David; Aneiros-Fernández, José; Hernández-Cortés, Pedro; Osuna, Antonio; Moreso, Francesc; Serón, Daniel; Oliver, Francisco J.; Del Moral, Raimundo G.

2009-01-01

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN). Materials and Methods Nuclear PARP-1 immunohistochemical expression was studied in 326 paraffin-embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury. Results PARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p = 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function. PMID:19784367

The effect of maleate induced proximal tubular dysfunction on the renal handling of Tc-99m DMSA in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Provoost, A.P.; Van Aken, M.

1984-01-01

In the healthy kidney Tc-99m DMSA accumulates in the proximal tubular cells. Consequently, impairment of the reabsorptive function of these cells may alter the renal handling of this static renal imaging agent. The authors investigated in rats the effects of a sodiummaleate (Ma) (2mmol/kg iv) induced proximal tubular dysfunction on the renal accumulation and excretion of Tc-99m DMSA. Such a treatment results in a moderate fall of the glomerular filtration rate, glycosuria, aminoaciduria and a tubular proteinuria. In 7 adult male Wistar rats, Tc-99m DMSA scans were taken before Ma, on the day of treatment, and 1 week thereafter. Themore » accumulation of Tc-99m DMSA in kidneys (Ki) and bladder (Bl) was determined at 1, 2, 4, and 24 hours after i.v. injection. The results, expressed as a percentage of the injected dose, are presented. The findings show that a reversible Ma induced impairment of the proximal reabsorptive capacity severely alters the renal tubular handling of Tc-99m DMSA. In contrast to the control situation, only a small fraction of the DMSA is retained in the kidney and the majority is transported directly to the urinary bladder. When similar alterations are observed in clinical Tc-99m DMSA scans, this may be an indication of an impairment of the proximal tubular function.« less

Loss of tubular creatinine secretion as the only sign of tubular proximal cell dysfunction in light chain proximal tubulopathy: A case report.

PubMed

Stehlé, Thomas; Vignon, Marguerite; Flamant, Martin; Figueres, Marie-Lucile; Rabant, Marion; Rodenas, Anita; Noël, Laure-Hélène; Arnulf, Bertrand; Vidal-Petiot, Emmanuelle

2016-06-01

Light chain proximal tubulopathy (LCPT) is a rare disease, characterized by cytoplasmic inclusions of light chain (usually kappa) immunoglobulins. Clinical presentation is usually a Fanconi syndrome. The proximal tubular dysfunction can be incomplete, and exceptional cases of LCPT without any tubular dysfunction have even been described. Here, we report a case of LCPT in which the only sign of proximal tubulopathy is the absence of secretion of creatinine, as assessed by the simultaneous measurement of renal clearance of creatinine and CrEDTA. The loss of tubular creatinine secretion as a sign of tubular proximal cell dysfunction ought to be identified in patients with light chain proximal tubulopathy as it leads to a clinically relevant underestimation of GFR by the creatinine-derived equations. The prevalence and prognostic significance of this particular proximal tubular damage in LCPT remain to be determined.

Evidence for an Intrinsic Renal Tubular Defect in Mice with Genetic Hypophosphatemic Rickets

PubMed Central

Cowgill, Larry D.; Goldfarb, Stanley; Lau, Kai; Slatopolsky, Eduardo; Agus, Zalman S.

1979-01-01

To investigate the role of parathyroid hormone (PTH) and(or) an intrinsic renal tubular reabsorptive defect for phosphate in mice with hereditary hypophosphatemic rickets, we performed clearance and micropuncture studies in hypophosphatemic mutants and nonaffected littermate controls. Increased fractional excretion of phosphate in mutants (47.2±4 vs. 30.8±2% in controls) was associated with reduced fractional and absolute reabsorption in the proximal convoluted tubule and more distal sites. Acute thyropara-thyroidectomy (TPTX) increased phosphate reabsorption in both mutants and controls with a fall in fractional phosphate excretion to ≅7.5% in both groups indicating that PTH modified the degree of phosphaturia in the intact mutants. Absolute reabsorption in the proximal tubule and beyond remained reduced in the mutants, however, possibly because of the reduced filtered load. Serum PTH levels were the same in intact mutants and normals as was renal cortical adenylate cyclase activity both before and after PTH stimulation. To evaluate the possibility that the phosphate wasting was caused by an intrinsic tubular defect that was masked by TPTX, glomerular fluid phosphate concentration was raised by phosphate infusion in TPTX mutants to levels approaching those of control mice. Phosphate excretion rose markedly and fractional reabsorption fell, but there was no change in absolute phosphate reabsorption in either the proximal tubule or beyond, indicating a persistent reabsorptive defect in the absence of PTH. We conclude that hereditary hypophosphatemia in the mouse is associated with a renal tubular defect in phosphate reabsorption, which is independent of PTH and therefore represents a specific intrinsic abnormality of phosphate transport. PMID:221535

Glomerular and Tubular Renal Function after Repeated Once-Daily Tobramycin Courses in Cystic Fibrosis Patients.

PubMed

Stehling, Florian; Büscher, Rainer; Grosse-Onnebrink, Jörg; Hoyer, Peter F; Mellies, Uwe

2017-01-01

Introduction . Antibiotic treatment regimens against Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients often include aminoglycoside antibiotics that may cause chronic renal failure after repeated courses. Aminoaciduria is an early marker of acute aminoglycoside-induced renal tubular dysfunction. We hypothesized that urinary amino acid reabsorption is decreased after repeated once-daily tobramycin therapies. Methods . In this prospective cross-sectional study creatinine clearance was estimated by the Schwartz and the Cockcroft-Gault formula. Tubular amino acid reabsorption was determined by ion exchange chromatography in 46 patients with CF who received multiple tobramycin courses (6.3 ± 10.1 (1-57)) in a once-daily dosing regimen and 10 who did not. Results . Estimated creatinine clearance employing the Cockcroft-Gault was mildly reduced in 17/46 (37%) of the patients who received tobramycin and 5/10 (50%) of the patients who did not but in none using the Schwartz formula. No association with lifetime tobramycin courses was found. Tubular amino acid reabsorption was not influenced by the amount of once-daily tobramycin courses. Conclusion . Clinically not significant reduction of eCCL occurred in a minority of CF patients. However, chronic tubular dysfunction was not present in patients with CF repeatedly treated with tobramycin in the once-daily dosing scheme.

The protective effect of menhaden oil in the oxidative damage and renal necrosis due to dietary choline deficiency.

PubMed

Ossani, Georgina P; Repetto, Marisa G; Boveris, Alberto; Monserrat, Alberto J

2013-02-26

Weanling rats fed a choline-deficient diet develop kidney oxidative damage, tubular and cortical kidney necrosis, renal failure and animal death. The effect of dietary menhaden oil was assayed on the mentioned sequence correlating oxidative stress with renal structure and function. Rats were fed ad libitum 4 different diets: (a) a choline-deficient diet with corn oil and sunflower hydrogenated oil as a source of fatty acids; (b) the same diet supplemented with choline; (c) a choline-deficient diet with menhaden oil as a source of fatty acids; and (d) the previous diet supplemented with choline. Animals were sacrificed at days 0, 2, 4 and 7. The histopathological study of the kidneys showed that renal necrosis was only observed at day 7 in choline-deficient rats receiving the vegetable oil diet, simultaneously with increased creatinine plasma levels. Homogenate chemiluminescence (BOOH-initiated chemiluminescence) and phospholipid oxidation indicate the development of oxidative stress and damage in choline-deficient rats fed vegetable oils as well as the protective effect of menhaden oil. Rats fed with the fish oil diet showed that oxidative stress and damage develop later, as compared with vegetable oil, with no morphological damage during the experimental period.

Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function

PubMed Central

Qi, Jia; Duan, Suyan; Huang, Zhimin; Zhang, Chengning; Wu, Lin; Zeng, Ming; Zhang, Bo; Wang, Ningning; Mao, Huijuan; Zhang, Aihua; Xing, Changying; Yuan, Yanggang

2017-01-01

Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI. PMID:28423497

Acceleration of recovery in acute renal failure: from cellular mechanisms of tubular repair to innovative targeted therapies.

PubMed

Abbate, M; Remuzzi, G

1996-05-01

Kidney repair from injury is a major focus of interest for research, both clinical and basic, in the field of acute renal failure. This is so because very little progress has been made during the past several years to improve mortality in hospitalized patients with acute renal failure despite the unique potential of the kidney for complete structural and functional recovery. Novel therapeutic options have recently emerged from the knowledge of molecular mechanisms of tissue injury after ischemia, including pathways of endothelial-leukocyte interaction and epithelial cell aggregation mediated by integrin molecules. These strategies are promising because they may target early mechanisms of leukocyte infiltration and tubular obstruction. However, it seems clear that additional interventions should address the reparative program that potentially leads to the full restoration of kidney structure and function. Thus, acceleration of repair from acute renal failure is achieved experimentally by growth factors which besides different renal actions seem to have in common the ability to stimulate proliferation of surviving tubular epithelial cells. We direct attention to cellular processes which characterize, and possibly have role in, renal repair from acute tubular injury as potential targets of therapy. In addition to proliferation, they include epithelial differentiation and apoptosis. Further investigation in the biology of repair should set the stage for rational design of targeted therapies which may accelerate the pace of recovery and hopefully decrease mortality in such a dramatic and potentially reversible setting.

Clinical and molecular aspects of distal renal tubular acidosis in children.

PubMed

Besouw, Martine T P; Bienias, Marc; Walsh, Patrick; Kleta, Robert; Van't Hoff, William G; Ashton, Emma; Jenkins, Lucy; Bockenhauer, Detlef

2017-06-01

Distal renal tubular acidosis (dRTA) is characterized by hyperchloraemic metabolic acidosis, hypokalaemia, hypercalciuria and nephrocalcinosis. It is due to reduced urinary acidification by the α-intercalated cells in the collecting duct and can be caused by mutations in genes that encode subunits of the vacuolar H + -ATPase (ATP6V1B1, ATP6V0A4) or the anion exchanger 1 (SLC4A1). Treatment with alkali is the mainstay of therapy. This study is an analysis of clinical data from a long-term follow-up of 24 children with dRTA in a single centre, including a genetic analysis. Of the 24 children included in the study, genetic diagnosis was confirmed in 19 patients, with six children having mutations in ATP6V1B1, ten in ATP6V0A4 and three in SLC4A1; molecular diagnosis was not available for five children. Five novel mutations were detected (2 in ATP6V1B1 and 3 in ATP6V0A4). Two-thirds of patients presented with features of proximal tubular dysfunction leading to an erroneous diagnosis of renal Fanconi syndrome. The proximal tubulopathy disappeared after resolution of acidosis, indicating the importance of following proximal tubular function to establish the correct diagnosis. Growth retardation with a height below -2 standard deviation score was found in ten patients at presentation, but persisted in only three of these children once established on alkali treatment. Sensorineural hearing loss was found in five of the six patients with an ATP6V1B1 mutation. Only one patient with an ATP6V0A4 mutation had sensorineural hearing loss during childhood. Nine children developed medullary cysts, but without apparent clinical consequences. Cyst development in this cohort was not correlated with age at therapy onset, molecular diagnosis, growth parameters or renal function. In general, the prognosis of dRTA is good in children treated with alkali.

Protective effect of hydroxytyrosol and its metabolite homovanillic alcohol on H(2)O(2) induced lipid peroxidation in renal tubular epithelial cells.

PubMed

Deiana, Monica; Incani, Alessandra; Rosa, Antonella; Corona, Giulia; Atzeri, Angela; Loru, Debora; Paola Melis, M; Assunta Dessì, M

2008-09-01

We investigated the capacity of hydroxytyrosol (HT), 3,4-dihydroxyphenylethanol, and homovanillic alcohol (HVA), 4-hydroxy-3-methoxy-phenylethanol, to inhibit H(2)O(2) induced oxidative damage in LLC-PK1, a porcine kidney epithelial cell line, studying the effect of H(2)O(2) on specific cell membrane lipid targets, unsaturated fatty acids and cholesterol. Exposure to H(2)O(2) induced a significant increase of the level of MDA together with a disruption of the membrane structure, with the loss of unsaturated fatty acids, cholesterol and alpha-tocopherol, and the formation of fatty acids hydroperoxides and 7-ketocholesterol. Pretreatment with HT protected renal cells from oxidative damage: the level of membrane lipids was preserved and there was no significant detection of oxidation products. HVA exerted a comparable activity, thus both HT and HVA were able to prevent in renal cells the lipid peroxidation process that plays a central role in tubular cell injury.

Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations

PubMed Central

Blázquez-Medela, Ana M.; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M.; Romero, Miguel; Duarte, Juan M.; López-Hernández, Francisco J.; López-Novoa, José M.; Martínez-Salgado, Carlos

2015-01-01

Abstract Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys. We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage. Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments. The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening. KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage. PMID:26469898

Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations.

PubMed

Blázquez-Medela, Ana M; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M; Romero, Miguel; Duarte, Juan M; López-Hernández, Francisco J; López-Novoa, José M; Martínez-Salgado, Carlos

2015-10-01

Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments.The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening.KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage.

Calcium-binding proteins annexin A2 and S100A6 are sensors of tubular injury and recovery in acute renal failure.

PubMed

Cheng, Chao-Wen; Rifai, Abdalla; Ka, Shuk-Man; Shui, Hao-Ai; Lin, Yuh-Feng; Lee, Wei-Hwa; Chen, Ann

2005-12-01

Rise in cellular calcium is associated with acute tubular necrosis, the most common cause of acute renal failure (ARF). The mechanisms that calcium signaling induce in the quiescent tubular cells to proliferate and differentiate during acute tubular necrosis have not been elucidated. Acute tubular necrosis induced in mice by single intravenous injection of uranyl nitrate and examined after 1, 3, 7, and 14 days. Renal function was monitored and kidneys were evaluated by histology, immunohistochemistry, Western blotting, in situ hybridization, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Models of folic acid induced-ARF and ischemic/reperfusion (I/R) injury were similarly investigated. Analysis of mRNA expression of intracellular calcium and phospholipid-binding proteins demonstrated selective expression of S100A6 and Annexin A2 (Anxa2) in the renal cortex with marked elevation on day 3, and gradually decline on day 7 and further attenuation on day 14. Similarly, the expression of both proteins, as demonstrated by immunohistochemistry and Western blot analysis, was increased and reached the peak level on day 7 and then gradually declined by day 14. Vimentin, a marker of dedifferentiated cells, was highly expressed during the recovery phase. Combined in situ hybridization immunohistochemistry revealed colocalization of both S100A6 and Anxa2 with proliferating cell nuclear antigen (PCNA). The universality of this phenomenon was confirmed in two other mouse acute tubular necrosis models, the ischemic-reperfusion injury and folic acid-induced ARF. Collectively, these findings demonstrate that S100A6 and Anxa2 expression, initiated in response to tubular injury, persist in parallel throughout the recovery process of tubular cells in acute renal failure.

Amelogenesis Imperfecta with Distal Renal Tubular Acidosis: A Novel Syndrome?

PubMed

Misgar, R A; Hassan, Z; Wani, A I; Bashir, M I

2017-01-01

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited dental enamel defects. It has rarely been reported in association with multiorgan syndromes and metabolic disorders. The metabolic disorders that have been reported in association with AI include hypocalciuria, impaired urinary concentrating ability, and Bartter-like syndrome. In literature, only three cases of AI and distal renal tubular acidosis (dRTA) have been described: two cases in adults and a solitary case in the pediatric age group. Here, we report a child with AI presenting with dRTA; to the best of our knowledge, our reported case is the only second such case in pediatric age group. Our case highlights the importance of recognizing the possibility of renal abnormalities in patients with AI as it will affect the long-term prognosis.

Disruption of gap junctions attenuates aminoglycoside-elicited renal tubular cell injury.

PubMed

Yao, Jian; Huang, Tao; Fang, Xin; Chi, Yuan; Zhu, Ying; Wan, Yigang; Matsue, Hiroyuki; Kitamura, Masanori

2010-08-01

Gap junctions play important roles in the regulation of cell phenotype and in determining cell survival after various insults. Here, we investigated the role of gap junctions in aminoglycoside-induced injury to renal tubular cells. Two tubular epithelial cell lines NRK-E52 and LLC-PK1 were compared for gap junction protein expression and function by immunofluorescent staining, Western blot and dye transfer assay. Cell viability after exposure to aminoglycosides was evaluated by WST assay. Gap junctions were modulated by transfection of the gap junction protein, connexin 43 (Cx43), use of Cx43 siRNA and gap junction inhibitors. NRK-E52 cells expressed abundant Cx43 and were functionally coupled by gap junctional intercellular communication (GJIC). Exposure of NRK-E52 cells to aminoglycosides, G418 and hygromycin, increased Cx43 phosphorylation and GJIC. The aminoglycosides also decreased cell viability that was prevented by gap junction inhibitors and Cx43 siRNA. LLC-PK1 cells were gap junction-deficient and resistant to aminoglycoside-induced cytotoxicity. Over-expression of a wild-type Cx43 converted LLC-PK1 cells to a drug-sensitive phenotype. The gap junction inhibitor alpha-glycyrrhetinic acid (alpha-GA) activated Akt in NRK-E52 cells. Inhibition of the Akt pathway enhanced cell toxicity to G418 and abolished the protective effects of alpha-GA. In addition, gentamycin-elicited cytotoxicity in NRK-E52 cells was also significantly attenuated by alpha-GA. Gap junctions contributed to the cytotoxic effects of aminoglycosides. Modulation of gap junctions could be a promising approach for prevention and treatment of aminoglycoside-induced renal tubular cell injury.

Effects of shiga toxin 2 on cellular regeneration mechanisms in primary and three-dimensional cultures of human renal tubular epithelial cells.

PubMed

Márquez, Laura B; Araoz, Alicia; Repetto, Horacio A; Ibarra, Fernando R; Silberstein, Claudia

2016-10-01

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes post-diarrheal Hemolytic Uremic Syndrome (HUS), which is one of the most common causes of acute renal failure in children in Argentine. The aim of the present work was to study the effects of Shiga toxin type 2 (Stx2) on regenerative mechanisms of primary cultures of human cortical renal tubular epithelial cells (HRTEC) and three-dimensional (3D) cultures of HRTEC. Primary cultures of HRTEC were able to develop tubular structures when grown in matrigel, which showed epithelial cells surrounding a central lumen resembling the original renal tubules. Exposure to Stx2 inhibited tubulogenesis in 3D-HRTEC cultures. Moreover, a significant increase in apoptosis, and decrease in cell proliferation was observed in tubular structures of 3D-HRTEC exposed to Stx2. A significant reduction in cell migration and vimentin expression levels was observed in HRTEC primary cultures exposed to Stx2, demonstrating that the holotoxin affected HRTEC dedifferentiation. Furthermore, a decreased number of cells expressing CD133 progenitor marker was found in HRTEC cultures treated with Stx2. The CD133 positive cells also expressed the Stx receptor globotriaosylceramide, which may explain their sensitivity to Stx2. In conclusion, Stx2 affects the regenerative processes of human renal tubular epithelial cells in vitro, by inhibiting cell dedifferentiation mechanisms, as well as tubules restoration. The development of 3D-HRTEC cultures that resemble original human renal proximal tubules is a novel in vitro model to study renal epithelial repair mechanisms after injury. Copyright © 2016 Elsevier Ltd. All rights reserved.

FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.

PubMed

Li, Fanghua; Liu, Zhiwen; Tang, Chengyuan; Cai, Juan; Dong, Zheng

2018-01-22

Cisplatin, a widely used cancer therapy drug, induces nephrotoxicity or acute kidney injury (AKI), but the underlying mechanism remains unclear, and renal protective approaches are not available. Fibroblast growth factor (FGF)21 is an endocrine factor that regulates glucose uptake, metabolism, and energy expenditure. However, recent work has also implicated FGF21 in cellular stress response under pathogenic conditions. The role and regulation of FGF21 in AKI are unclear. Here, we show that FGF21 was dramatically induced during cisplatin treatment of renal tubular cells in vitro and mouse kidneys in vivo. The inductive response was suppressed by pifithrin (a pharmacological inhibitor of P53), suggesting a role of P53 in FGF21 induction. In cultured renal tubular cells, knockdown of FGF21 aggravated cisplatin-induced apoptosis, whereas supplementation of recombinant FGF21 was protective. Consistently, recombinant FGF21 alleviated cisplatin-induced kidney dysfunction, tissue damage, and tubular apoptosis in mice. Mechanistically, FGF21 suppressed P53 induction and activation during cisplatin treatment. Together, these results indicate that FGF21 is induced during cisplatin nephrotoxicity to protect renal tubules, and recombinant FGF21 may have therapeutic potential.-Li, F., Liu, Z., Tang, C., Cai, J., Dong, Z. FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.

Lack of passive transfer of renal tubulointerstitial disease by serum or monoclonal antibody specific for renal tubular antigens in the mouse.

PubMed

Evans, B D; Dilwith, R L; Balaban, S L; Rudofsky, U H

1988-01-01

Mice immunized with rabbit renal basement membranes form autoantibodies to their kidney glomerular and tubular basement membranes (GBM/TBM). Development of renal tubular disease (RTD) consists of deposition of autoantibodies along the GBM/TBM with the inter- and intratubular accumulation of lymphocytes and macrophages and destruction of the TBM. Transfer of this disease in mice with either serum or monoclonal antibodies, however, has been difficult to demonstrate and, therefore, attempts were made to confirm a report that RTD is passively transferred by anti-TBM autoantibodies. Using the revised protocol in this later report, we found that 12 weeks after transfer autoantibodies were deposited along the GBM and/or TBM of the recipients, yet RTD was not observed. Although qualitative and quantitative characteristics of the antibody may play a role in the pathogenesis in the murine model of RTD, we could not obtain evidence to support and confirm this study.

Experimental drug-induced changes in renal function and biodistribution of /sup 99m/Tc-MDP

DOE Office of Scientific and Technical Information (OSTI.GOV)

McAfee, J.G.; Singh, A.; Roskopf, M.

Increased renal uptake of /sup 99m/Tc methylene diphosphonate (MDP) was observed irregularly in rats after methotrexate, vincristine or gentamicin, administered separately. Cisplatin regularly induced a dose-related increased MDP uptake which correlated with the degree of tubular damage histologically. The augmented MDP renal uptake was not consistently accompanied by a decreased clearance of simultaneously injected I-131 Hippuran, particularly at lower drug dose levels. This observation agreed with previous evidence that the mechanisms of tubular transport of diphosphonates and organic acids like Hippuran are different. At higher dose levels, the augmented MDP uptake was accompanied by increased renal calcium, hypophosphatemia, elevated serummore » urea nitrogen and creatinine, and only occasional, mild hypercalcemia. The magnitude of the increased renal uptake of MDP observed could not be explained by alterations in iron metabolism or by dehydration. Drug-induced renal retention of MDP by a factor of 2 or more above normal appears to be a useful indicator of tubular damage when other parameters of renal function are sometimes normal.« less

SPIRULINA PLATENSIS PROTECTS AGAINST RENAL INJURY IN RATS WITH GENTAMICIN-INDUCED ACUTE TUBULAR NECROSIS

PubMed Central

Avdagić, Nesina; Ćosović, Esad; Nakaš-Ićindić, Emina; Mornjaković, Zakira; Začiragić, Asija; Hadžović-Džuvo, Almira

2008-01-01

The present study was carried out to evaluate the renoprotective antioxidant effect of Spirulina platensis on gentamicin-induced acute tubular necrosis in rats. Albino-Wistar rats, (9male and 9 female), weighing approximately 250 g, were used for this study. Rats were randomly assigned to three equal groups. Control group received 0,9 % sodium chloride intraperitoneally for 7 days at the same volume as gentamicin group. Gentamicin group was treated intraperitoneally with gentamicin, 80mg/kg daily for 7 days. Gentamicin+spirulina group received Spirulina platensis 1000 mg/kg orally 2 days before and 7 days concurrently with gentamicin (80mg/kg i.p.). Nephrotoxicity was assessed by measuring plasma nitrite concentration, stabile metabolic product of nitric oxide with oxygen. Plasma nitrite concentration was determined by colorimetric method using Griess reaction. For histological analysis kidney specimens were stained with hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) stain. Plasma nitrite concentration and the level of kidney damage were significantly higher in gentamicin group in comparison both to the control and gentamicin+spirulina group. Spirulina platensis significantly lowered the plasma nitrite level and attenuated histomorphological changes related to renal injury caused by gentamicin. Thus, the results from present study suggest that Spirulina platensis has renoprotective potential in gentamicin-induced acute tubular necrosis possibly due to its antioxidant properties. PMID:19125703

Spirulina platensis protects against renal injury in rats with gentamicin-induced acute tubular necrosis.

PubMed

Avdagić, Nesina; Cosović, Esad; Nakas-Ićindić, Emina; Mornjaković, Zakira; Zaciragić, Asija; Hadzović-Dzuvo, Almira

2008-11-01

The present study was carried out to evaluate the renoprotective antioxidant effect of Spirulina platensis on gentamicin-induced acute tubular necrosis in rats. Albino-Wistar rats, (9male and 9 female), weighing approximately 250 g, were used for this study. Rats were randomly assigned to three equal groups. Control group received 0,9 % sodium chloride intraperitoneally for 7 days at the same volume as gentamicin group. Gentamicin group was treated intraperitoneally with gentamicin, 80 mg/kg daily for 7 days. Gentamicin+spirulina group received Spirulina platensis 1000 mg/kg orally 2 days before and 7 days concurrently with gentamicin (80 mg/kg i.p.). Nephrotoxicity was assessed by measuring plasma nitrite concentration, stabile metabolic product of nitric oxide with oxygen. Plasma nitrite concentration was determined by colorimetric method using Griess reaction. For histological analysis kidney specimens were stained with hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) stain. Plasma nitrite concentration and the level of kidney damage were significantly higher in gentamicin group in comparison both to the control and gentamicin+spirulina group. Spirulina platensis significantly lowered the plasma nitrite level and attenuated histomorphological changes related to renal injury caused by gentamicin. Thus, the results from present study suggest that Spirulina platensis has renoprotective potential in gentamicin-induced acute tubular necrosis possibly due to its antioxidant properties.

Comparison of four decontamination treatments on porcine renal decellularized extracellular matrix structure, composition, and support of human renal cortical tubular epithelium cells.

PubMed

Poornejad, Nafiseh; Nielsen, Jeffery J; Morris, Ryan J; Gassman, Jason R; Reynolds, Paul R; Roeder, Beverly L; Cook, Alonzo D

2016-03-01

Engineering whole organs from porcine decellularized extracellular matrix and human cells may lead to a plentiful source of implantable organs. Decontaminating the porcine decellularized extracellular matrix scaffolds is an essential step prior to introducing human cells. However, decontamination of whole porcine kidneys is a major challenge because the decontamination agent or irradiation needs to diffuse deep into the structure to eliminate all microbial contamination while minimizing damage to the structure and composition of the decellularized extracellular matrix. In this study, we compared four decontamination treatments that could be applicable to whole porcine kidneys: 70% ethanol, 0.2% peracetic acid in 1 M NaCl, 0.2% peracetic acid in 4% ethanol, and gamma (γ)-irradiation. Porcine kidneys were decellularized by perfusion of 0.5% (w/v) aqueous solution of sodium dodecyl sulfate and the four decontamination treatments were optimized using segments (n = 60) of renal tissue to ensure a consistent comparison. Although all four methods were successful in decontamination, γ-irradiation was very damaging to collagen fibers and glycosaminoglycans, leading to less proliferation of human renal cortical tubular epithelium cells within the porcine decellularized extracellular matrix. The effectiveness of the other three optimized solution treatments were then all confirmed using whole decellularized porcine kidneys (n = 3). An aqueous solution of 0.2% peracetic acid in 1 M NaCl was determined to be the best method for decontamination of porcine decellularized extracellular matrix. © The Author(s) 2015.

Congenital ureteropelvic junction obstruction: physiopathology, decoupling of tout court pelvic dilatation-obstruction semantic connection, biomarkers to predict renal damage evolution.

PubMed

Alberti, C

2012-02-01

The widespread use of fetal ultrasonography results in a frequent antenatally observation of hydronephrosis, ureteropelvic junction obstruction (UPJO) accounting for the greatest fraction of congenital obstructive nephropathy. UPJO may be considered, in most cases, as a functional obstructive condition, depending on defective fetal smooth muscle/nerve development at this level, with lack of peristaltic wave propagation--aperistaltic segment--and, therefore, poor urine ejection from the renal pelvis into the ureter. The UPJO-related physiopathologic events are, at first, the compliant dilatation of renal pelvis that, acting as hydraulic buffer, protects the renal parenchyma from the rising intrapelvic pressure-related potential damages, and, subsequently, beyond such phase of dynamic balance, the tubular cell stretch-stress induced by increased intratubular pressure and following parenchymal inflammatory lesions: inflammatory infiltrates, fibroblast proliferation, activation of myofibroblasts, tubulo-interstitial fibrosis. Reactive oxygen species (ROS), nitric oxide (NO), several chemo- and cytokines, growth factors, prostaglandins and eicosanoids, angiotensin-II are the main pathogenetic mediators of the obstructive nephropathy. Apoptosis of tubular cells is the major cause of the tubular atrophy, together with epithelial-mesenchymal transdifferentiation. Some criticisms on tout court semantic renal pelvis dilatation-obstruction connection have been raised considering that the renal pelvis expansion isn't, in any case, linked to an ostructive condition, as it may be verified by diuretic (furosemide) renogram together with scintiscan-based evaluation of differential renal function. In this regard, rather than repetitive invasive nuclear procedures that expose the children to ionizing radiations, an intriguing noninvasive strategy, based on the evaluation of urinary biomarkers and urinary proteome, can define the UPJO-related possible progress of parenchymal lesions

Renal Integrin-Linked Kinase Depletion Induces Kidney cGMP-Axis Upregulation: Consequences on Basal and Acutely Damaged Renal Function

PubMed Central

Cano-Peñalver, José Luis; Griera, Mercedes; García-Jerez, Andrea; Hatem-Vaquero, Marco; Ruiz-Torres, María Piedad; Rodríguez-Puyol, Diego; de Frutos, Sergio; Rodríguez-Puyol, Manuel

2015-01-01

Soluble guanylyl cyclase (sGC) is activated by nitric oxide (NO) and produces cGMP, which activates cGMP-dependent protein kinases (PKG) and is hydrolyzed by specific phosphodiesterases (PDE). The vasodilatory and cytoprotective capacity of cGMP-axis activation results in a therapeutic strategy for several pathologies. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix and intracellular signaling pathways, may modulate the expression and functionality of the cGMP-axis–related proteins. We introduce ILK as a novel modulator in renal homeostasis as well as a potential target for cisplatin (CIS)-induced acute kidney injury (AKI) improvement. We used an adult mice model of depletion of ILK (cKD-ILK), which showed basal increase of sGC and PKG expressions and activities in renal cortex when compared with wildtype (WT) littermates. Twenty-four h activation of sGC activation with NO enhanced the filtration rate in cKD-ILK. During AKI, cKD-ILK maintained the cGMP-axis upregulation with consequent filtration rates enhancement and ameliorated CIS-dependent tubular epithelial-to-mesenchymal transition and inflammation and markers. To emphasize the role of cGMP-axis upregulation due to ILK depletion, we modulated the cGMP axis under AKI in vivo and in renal cultured cells. A suboptimal dose of the PDE inhibitor ZAP enhanced the beneficial effects of the ILK depletion in AKI mice. On the other hand, CIS increased contractility-related events in cultured glomerular mesangial cells and necrosis rates in cultured tubular cells; ILK depletion protected the cells while sGC blockade with ODQ fully recovered the damage. PMID:26562149

Disruption of gap junctions attenuates aminoglycoside-elicited renal tubular cell injury

PubMed Central

Yao, Jian; Huang, Tao; Fang, Xin; Chi, Yuan; Zhu, Ying; Wan, Yigang; Matsue, Hiroyuki; Kitamura, Masanori

2010-01-01

BACKGROUND AND PURPOSE Gap junctions play important roles in the regulation of cell phenotype and in determining cell survival after various insults. Here, we investigated the role of gap junctions in aminoglycoside-induced injury to renal tubular cells. EXPERIMENTAL APPROACH Two tubular epithelial cell lines NRK-E52 and LLC-PK1 were compared for gap junction protein expression and function by immunofluorescent staining, Western blot and dye transfer assay. Cell viability after exposure to aminoglycosides was evaluated by WST assay. Gap junctions were modulated by transfection of the gap junction protein, connexin 43 (Cx43), use of Cx43 siRNA and gap junction inhibitors. KEY RESULTS NRK-E52 cells expressed abundant Cx43 and were functionally coupled by gap junctional intercellular communication (GJIC). Exposure of NRK-E52 cells to aminoglycosides, G418 and hygromycin, increased Cx43 phosphorylation and GJIC. The aminoglycosides also decreased cell viability that was prevented by gap junction inhibitors and Cx43 siRNA. LLC-PK1 cells were gap junction-deficient and resistant to aminoglycoside-induced cytotoxicity. Over-expression of a wild-type Cx43 converted LLC-PK1 cells to a drug-sensitive phenotype. The gap junction inhibitor α-glycyrrhetinic acid (α-GA) activated Akt in NRK-E52 cells. Inhibition of the Akt pathway enhanced cell toxicity to G418 and abolished the protective effects of α-GA. In addition, gentamycin-elicited cytotoxicity in NRK-E52 cells was also significantly attenuated by α-GA. CONCLUSION AND IMPLICATIONS Gap junctions contributed to the cytotoxic effects of aminoglycosides. Modulation of gap junctions could be a promising approach for prevention and treatment of aminoglycoside-induced renal tubular cell injury. PMID:20649601

Neural control of renal function: role of renal alpha adrenoceptors.

PubMed

DiBona, G F

1985-01-01

Adrenoceptors of various subtypes mediate the renal functional responses to alterations in efferent renal sympathetic nerve activity, the neural component, and renal arterial plasma catecholamine concentrations, the humoral component, of the sympathoadrenergic nervous system. Under normal physiologic as well as hypertensive conditions, the influence of the renal sympathetic nerves predominates over that of circulating plasma catecholamines. In most mammalian species, increases in efferent renal sympathetic nerve activity elicit renal vasoconstrictor responses mediated predominantly by renal vascular alpha-1 adrenoceptors, increases in renin release mediated largely by renal juxtaglomerular granular cell beta-1 adrenoceptors with involvement of renal vascular alpha-1 adrenoceptors only when renal vasoconstriction occurs, and direct increases in renal tubular sodium and water reabsorption mediated predominantly by renal tubular alpha-1 adrenoceptors. In most mammalian species, alpha-2 adrenoceptors do not play a significant role in the renal vascular or renin release responses to renal sympathoadrenergic stimulation. Although renal tubular alpha-2 adrenoceptors do not mediate the increases in renal tubular sodium and water reabsorption produced by increases in efferent renal sympathetic nerve activity, they may be involved through their inhibitory effect on adenylate cyclase in modulating the response to other hormonal agents that influence renal tubular sodium and water reabsorption via stimulation of adenylate cyclase.

Ochratoxin A induced premature senescence in human renal proximal tubular cells.

PubMed

Yang, Xuan; Liu, Sheng; Huang, Chuchu; Wang, Haomiao; Luo, Yunbo; Xu, Wentao; Huang, Kunlun

2017-05-01

Ochratoxin A (OTA) has many nephrotoxic effects and is a promising compound for the study of nephrotoxicity. Human renal proximal tubular cells (HKC) are an important model for the study of renal reabsorption, renal physiology and pathology. Since the induction of OTA in renal senescence is largely unknown, whether OTA can induce renal senescence, especially at a sublethal dose, and the mechanism of OTA toxicity remain unclear. In our study, a sublethal dose of OTA led to an enhanced senescent phenotype, β-galactosidase staining and senescence associated secretory phenotype (SASP). Cell cycle arrest and cell shape alternations also confirmed senescence. In addition, telomere analysis by RT-qPCR allowed us to classify OTA-induced senescence as a premature senescence. Western blot assays showed that the p53-p21 and the p16-pRB pathways and the ezrin-associated cell spreading changes were activated during the OTA-induced senescence of HKC. In conclusion, our results demonstrate that OTA promotes the senescence of HKC through the p53-p21 and p16-pRB pathways. The understanding of the mechanisms of OTA-induced senescence is critical in determining the role of OTA in cytotoxicity and its potential carcinogenicity. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

1,[Formula: see text]2,[Formula: see text]3,[Formula: see text]4,[Formula: see text]6-Penta-O-Galloyl-β-D-Glucose from Galla rhois Ameliorates Renal Tubular Injury and Microvascular Inflammation in Acute Kidney Injury Rats.

PubMed

Park, Ji Hun; Kho, Min Chol; Oh, Hyun Cheol; Kim, Youn Chul; Yoon, Jung Joo; Lee, Yun Jung; Kang, Dae Gill; Lee, Ho Sub

2018-05-13

Renal ischemia-reperfusion injury (IRI), an important cause of acute kidney injury (AKI), causes increased renal tubular injury and microvascular inflammation. 1,[Formula: see text]2,[Formula: see text]3,[Formula: see text]4,[Formula: see text]6-penta-O-galloyl-[Formula: see text]-D-glucose (PGG) from Galla rhois has anticancer, anti-oxidation and angiogenesis effects. We examined protective effects of PGG on IRI-induced acute AKI. Clamping both renal arteries for 45[Formula: see text]min induced isechemia and then reperfusion. Treatment with PGG (10[Formula: see text]mg/kg/day and 50[Formula: see text]mg/kg/day for four days) significantly ameliorated urine volume, urine osmolality, creatinine clearance (Ccr) and blood urea nitrogen (BUN). In addition, PGG increased aquaporine 1/2/3, Na[Formula: see text]-K[Formula: see text]-ATPase and urea transporter (UT-B) and decreased ICAM-1, MCP-1, and HMGB-1 expression. In this histopathologic study, PGG improved glomerular and tubular damage. Immunohistochemistry results showed that PGG increased aquaporine 1/2, and Na[Formula: see text]-K[Formula: see text] ATPase and decreased ICAM-1 expression. These findings suggest that PGG ameliorates tubular injury including tubular dysfunction and microvascular inflammation in IRI-induced AKI rats.

Polycystin-1 Binds Par3/aPKC and Controls Convergent Extension During Renal Tubular Morphogenesis

PubMed Central

Castelli, Maddalena; Boca, Manila; Chiaravalli, Marco; Ramalingam, Harini; Rowe, Isaline; Distefano, Gianfranco; Carroll, Thomas; Boletta, Alessandra

2013-01-01

Several organs, including lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintanance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1 (PC-1), a large receptor of unknown function. Here we demonstrate that PC-1 plays an essential role in establishment of correct tubular diameter during nephron development. PC-1 associates with Par3 favoring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a program of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis and in renal cyst formation. Our data define PC-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis. PMID:24153433

Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis

NASA Astrophysics Data System (ADS)

Castelli, Maddalena; Boca, Manila; Chiaravalli, Marco; Ramalingam, Harini; Rowe, Isaline; Distefano, Gianfranco; Carroll, Thomas; Boletta, Alessandra

2013-10-01

Several organs, including the lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintenance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1, a large receptor of unknown function. Here we demonstrate that PC-1 has an essential role in the establishment of correct tubular diameter during nephron development. Polycystin-1 associates with Par3 favouring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a programme of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis, and in renal cyst formation. Our data define Polycystin-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis.

Reduction of high-energy shock-wave-induced renal tubular injury by selenium.

PubMed

Strohmaier, W L; Lahme, S; Weidenbach, P M; Bichler, K H

1999-10-01

In shock-wave-induced renal injury cavitation-generated free radicals play an important role. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of selenium, a free radical scavenger, in shock-wave-induced tubular cell injury. Suspensions of MDCK cells (33 x 10(6) cells/ml) were placed in small containers (volume 1.1 ml) for shock wave exposure. Two groups of 12 containers each were examined: (1) control (no medication), (2) selenium (0.4 microg/ml nutrient medium). Six containers in each group were exposed to shock waves (impulse rate 256, frequency 60 Hz, generator voltage 18 kV), while the other six containers in each group served as a control. After shock wave exposure, the concentration of cellular enzymes such as lactate dehydrogenase (LDH), N-acetyl-beta-glucosaminidase (NAG), glutamate oxaloacetate transaminase (GOT) and glutamate lactate dehydrogenase (GLDH) in the nutrient medium was examined. Following shock wave exposure there was a significant rise in LDH, NAG, GOT and GLDH concentrations. Selenium reduced this enzyme leakage significantly. Thus we conclude that selenium protects renal tubular cells against shock-wave-induced injury. Since selenium is an essential part of glutathione peroxidase, this effect seems to be mediated by a reduction in reactive oxygen species.

Hydraulic pressure inducing renal tubular epithelial-myofibroblast transdifferentiation in vitro.

PubMed

Li, Fei-yan; Xie, Xi-sheng; Fan, Jun-ming; Li, Zi; Wu, Jiang; Zheng, Rong

2009-09-01

The effects of hydraulic pressure on renal tubular epithelial-myofibroblast transdifferentiation (TEMT) were investigated. We applied hydraulic pressure (50 cm H2O) to normal rat kidney tubular epithelial cells (NRK52E) for different durations. Furthermore, different pressure magnitudes were applied to cells. The morphology, cytoskeleton, and expression of myofibroblastic marker protein and transforming growth factor-beta1 (TGF-beta1) of NRK52E cells were examined. Disorganized actin filaments and formation of curling clusters in actin were seen in the cytoplasm of pressurized cells. We verified that de novo expression of alpha-smooth muscle actin induced by pressure, which indicated TEMT, was dependent on both the magnitude and duration of pressure. TGF-beta1 expression was significantly upregulated under certain conditions, which implies that the induction of TEMT by hydraulic pressure is related with TGF-beta1. We illustrate for the first time that hydraulic pressure can induce TEMT in a pressure magnitude- and duration-dependent manner, and that this TEMT is accompanied by TGF-beta1 secretion.

Comparison of two models for evaluation histopathology of experimental renal ischemia.

PubMed

Tirapelli, L F; Barione, D F; Trazzi, B F M; Tirapelli, D P C; Novas, P C; Silva, C S; Martinez, M; Costa, R S; Tucci, S; Suaid, H J; Cologna, A J; Martins, A C P

2009-12-01

Renal ischemia/reperfusion (I/R) injury is one of the frequent causes of acute renal failure (ARF) due to the complex, interrelated sequence of events, that result in damage to and death of kidney cells. Cells of the proximal tubular epithelium are especially susceptible to I/R injury, leading to acute tubular necrosis, which plays a pivotal role in the pathogenesis of ARF. Several models have been explicated to assess morphological changes, including those of Jabonski et al. and Goujon et al. We compared the 2 models for histopathological evaluation of 30- or 120-minute periods of renal ischemia followed by 24-hour reperfusion in rats. Several changes were observed after application of the 2 models: proximal tubular cell necrosis, loss of brush border, vacuolization, denudation of tubular basement membrane as a consequence of flattening of basal cells, and presence of intratubular exfoliated cells in the lumen of proximal convoluted tubules at various stages of degeneration (karyorexis, kariopyknosis and karyolysis). Evaluating tubular lesions after 2 periods of experimental ischemia with light microscopy allowed us to conclude that the Goujon classification better characterized the main changes in cortical renal tubules after ischemia.

Biomarkers-a potential route for improved diagnosis and management of ongoing renal damage.

PubMed

Oberbauer, R

2008-12-01

Currently, the identification and validation of biomarkers of kidney injury is among the top priorities of many diagnostic biotechnology companies as well as academic research institutes. Specifically, in renal transplantation, validated biomarkers of tissue injury with good discriminatory power between the various renal compartments and the underlying pathophysiology are desired, because sequential allograft biopsies are limited in number and cannot be used as a screening tool. Given the high demands on these markers, it is not surprising that none of those currently under evaluation has been thoroughly validated for a specific entity. Published biomarker candidates for early tubular damage include neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, soluble CD30, perforin, and granzyme B. Recently, C4d flow panel reactive antibodies were evaluated as biomarkers for humoral alloimmune responses. Additional biomarkers such as FOXP3 and kidney injury molecule 1 have been studied in the maintenance phase of renal transplantation. Given the complex prerequisites, it is not surprising that no biomarker panel has been sufficiently validated for clinical use. However, in the near future a biomarker for use as an indicator of renal tubule cell injury will be available. Troponin T or transaminase of the kidney may then at least be used to differentiate between functional renal failure (equivalent to a rise in creatinine) and intrinsic kidney injury.

Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

PubMed Central

Zhou, Yang; Fang, Li; Jiang, Lei; Wen, Ping; Cao, Hongdi; He, Weichun; Dai, Chunsun; Yang, Junwei

2012-01-01

Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling. PMID:22761883

Effect of vitamin E on reversibility of renal function following discontinuation of colistin in rats: Histological and biochemical investigations.

PubMed

Ghlissi, Zohra; Hakim, Ahmed; Mnif, Hela; Kallel, Rim; Zeghal, Khaled; Boudawara, Tahiya; Sahnoun, Zouheir

2018-01-01

This study was carried out to evaluate spontaneous renal regeneration after stopping colistin methanesulfonate (CMS), which induces tubular damage, and the curative effect of Vitamin E (vit E) in rats. Animals were given the following: sterile saline (n = 6), 300,000 IU/kg/ day of CMS (n = 24), or 450,000 IU/kg/day of CMS (n = 24) for seven days. Each CMS group was subdivided into four subgroups (n = 6) and sacrificed as follows: (i) 12 h after stopping CMS, (ii) two weeks after stopping CMS, (iii) two weeks after stopping treatment with vit E, and (iv) two weeks after stopping treatment with olive oil. Subsequently, plasma creatinine (pCr), urine N-acetyl-b-D-glucosaminidase (NAG), renal tissue level of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GSH), and renal histology were tested. CMS-induced tubular damage increased the NAG and MDA levels and decreased the SOD and GSH activities. After two weeks of stopping CMS, there was no significant renal recovery. However, treatment with vit E improved tubular regeneration and reduced the biochemical impairments. Two weeks might not be long enough for significant spontaneous renal regeneration. Improvement of renal parameters by vit E could be explained by the reduction of oxidative stress damage.

Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy

PubMed Central

Jheng, Huei-Fen; Tsai, Pei-Jane; Chuang, Yi-Lun; Shen, Yi-Ting; Tai, Ting-An; Chen, Wen-Chung; Chou, Chuan-Kai; Ho, Li-Chun; Tang, Ming-Jer; Lai, Kuei-Tai A.; Sung, Junne-Ming; Tsai, Yau-Sheng

2015-01-01

ABSTRACT Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4−/− mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN. PMID:26398934

[Plasma cell dyscrasias and renal damage].

PubMed

Pasquali, Sonia; Iannuzzella, Francesco; Somenzi, Danio; Mattei, Silvia; Bovino, Achiropita; Corradini, Mattia

2012-01-01

Kidney damage caused by immunoglobulin free light chains in the setting of plasma cell dyscrasias is common and may involve all renal compartments, from the glomerulus to the tubulointerstitium, in a wide variety of histomorphological and clinical patterns. The knowledge of how free light chains can promote kidney injury is growing: they can cause functional changes, be processed and deposited, mediate inflammation, apoptosis and fibrosis, and obstruct nephrons. Each clone of the free light chain is unique and its primary structure and post-translation modification can determine the type of renal disease. Measurement of serum free light chain concentrations and calculation of the serum kappa/lambda ratio, together with renal biopsy, represent essential diagnostic tools. An early and correct diagnosis of renal lesions due to plasma cell dyscrasias will allow early initiation of disease-specific treatment strategies. The treatment of free light chain nephropathies is evolving and knowledge of the pathways that promote renal damage should lead to further therapeutic developments.

Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatment.

PubMed

Sromicki, Jerzy Jan; Hess, Bernhard

2017-06-01

Chronic acid retention is known to promote bone dissolution. In this study, 23 % of patients with osteopenia/osteoporosis were diagnosed with abnormal distal renal tubular acidification (dRTA), a kidney dysfunction leading to chronic acid retention. Treating those patients with alkali-therapy shows improvement in bone density. To evaluate the prevalence of abnormal distal renal tubular acidification in patients with low bone mass (LBM) and the impact of additional alkali treatment on bone density in patients with concomitant LBM and dRTA,183 patients referred for metabolic evaluation of densitometrically proven low bone mass were screened for abnormal distal renal tubular acidification between 2006 and 2013. In all LBM urine pH (U-pH) was measured in the 2nd morning urines after 12 h of fasting. If U-pH was ≥5.80, LBM underwent a 1-day ammonium chloride loading, and U-pH was remeasured the next morning. If U-pH after acid loading did not drop below 5.45, patients were diagnosed with abnormal distal renal tubular acidification. Normal values were obtained from 21 healthy controls. All LBM with dRTA were recommended alkali citrate in addition to conventional therapy of LBM, and follow-up DXAs were obtained until 2014. 85 LBM underwent NH 4 Cl loading. 42 LBM patients were diagnosed with incomplete dRTA (idRTA; prevalence 23.0 %). During follow-up (1.6-8 years) of idRTA-LBM patients, subjects adhering to alkali treatment tended to improve BMD at all sites measured, whereas BMD of non-adherent idRTA patients worsened/remained unchanged. (1) About one out of four patients with osteopenia/osteoporosis has idRTA. (2) Upon NH 4 Cl loading, idRTA patients do not lower urine pH normally, but show signs of increased acid-buffering by bone dissolution. (3) In idRTA patients with low bone mass on conventional therapy, additional long-term alkali treatment improves bone mass at lumbar spine and potentially at other bone sites. (4) All patients with low bone mass undergoing

Acute and cumulative effects of carboplatin on renal function.

PubMed Central

Sleijfer, D. T.; Smit, E. F.; Meijer, S.; Mulder, N. H.; Postmus, P. E.

1989-01-01

Carboplatin, a cisplatinum analogue, has no reported nephrotoxicity in phase I/II studies, assessed by creatinine clearance. We prospectively determined renal function in 10 untreated lung cancer patients with normal baseline renal function, treated with carboplatin 400 mg m-2 day 1 and vincristine 2 mg day 1 and 8 every 4 weeks (max. five cycles) by means of clearance studies with 125I-sodium thalamate and 131I-hippurate to determine GFR and ERPF respectively. Tubular damage was monitored by excretion of tubular enzymes and relative beta 2-microglobulin clearance. During the first course no changes in renal function were seen. After the second course a significant fall in GFR and ERPF started, ultimately leading to a median decrease in GFR of 19.0% (range 6.8-38.7%) and in ERPF of 14% (range 0-38.9%). No increases in the excretion of tubular enzymes or changes in the relative beta 2-microglobulin clearances were seen. We conclude from our data that carboplatin causes considerable loss of renal function. Monitoring renal function in patients treated with multiple courses of carboplatin is warranted. PMID:2679841

Bcl-2 protects tubular epithelial cells from ischemia/reperfusion injury by dual mechanisms.

PubMed

Isaka, Y; Suzuki, C; Abe, T; Okumi, M; Ichimaru, N; Imamura, R; Kakuta, Y; Matsui, I; Takabatake, Y; Rakugi, H; Shimizu, S; Takahara, S

2009-01-01

Ischemia/reperfusion (I/R) injury, which induces extensive loss of tubular epithelial cells, is associated with delayed graft function following kidney transplantation. Recent reports have suggested that cell death by I/R injury occurs by autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, as well as by apoptosis. Recently, we demonstrated that overexpression of the anti-apoptotic factor, Bcl-2, inhibited tubular apoptosis and subsequent tubulointerstitial damage after I/R injury. Autophagy is also observed in cells undergoing cell death in several diseases. Therefore, we hypothesized that increased Bcl-2 protein may protect tubular epithelial cells by suppressing autophagy and inhibiting apoptosis. In the present study, a transgenic mouse model (LC3-GFP TG) in which autophagosomes are labeled with LC3-GFP and Bcl-2/LC3-GFP double transgenic mice (Bcl-2/LC3-GFP TG) were used to examine the effect of Bcl-2 on I/R-induced autophagy. I/R injury, which is associated with marked disruption of normal tubular morphology, promoted the formation of LC3-GFP dots, representing extensively induced autophagosomes. On electron microscopy, the autophagosomes contained mitochondria in I/R-injured tubular epithelial cells. In contrast, Bcl-2 augmentation suppressed the formation of autophagosomes and there was less tubular damage. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R injury by suppressing autophagosomal degradation and inhibiting tubular apoptosis.

THE FAILURE OF CHLOROFORM ADMINISTERED IN THE DRINKING WATER TO INDUCE RENAL TUBULAR CELL NEOPLASIA IN MALE F344/N RATS

EPA Science Inventory

The failure of chloroform administered in drinking water to induce renal tubular cell neoplasia in male F344/N rats

Chloroform (TCM) has been demonstrated to be a renal carcinogen in the male Osborne-
Mendel rat when administered either by corn oil gavage or in drin...

Complete renal tubular acidosis late after kidney transplantation.

PubMed

Schwarz, Christoph; Benesch, Thomas; Kodras, Katharina; Oberbauer, Rainer; Haas, Martin

2006-09-01

Neither the prevalence nor the associated risk factors of late post-transplant renal tubular acidosis (RTA) are known. We conducted a cross-sectional study with 576 patients for more than 12 months after kidney transplantation, and a glomerular filtration rate (GFR) >40 ml/min. RTA was diagnosed by measurement of the urine anionic gap, urine pH and plasma potassium during acidosis, and fractional bicarbonate excretion after bicarbonate loading. Uni- and multi-variable analysis were used to isolate factors associated with post-transplant RTA, and with the different RTA subtypes. All patients (n = 76) had distal post-transplant RTA. A significant association with the presence of RTA was found for the intake of tacrolimus or renin-angiotensin-aldosterone blockers, the Parathyroid hormone level and the GFR. Type Ia (classic, distal), type Ib (hyperkalaemic, voltage-dependent), rate-limited and type IV RTA were present in 37, 14, 21 and 28% of the patients. Acute transplant rejection was the only significant different parameter between the RTA subtypes and more often present in patients with type Ia or Ib RTA. We conclude that a significant fraction of stable long-term renal transplant recipients with adequate graft function develop post-transplant RTA, with a preponderance for type Ia and type IV, and absence of type II. In addition, acute transplant rejection seems to have an influence on the subtype of RTA present post-transplantation.

Tubular Epithelial NF-κB Activity Regulates Ischemic AKI

PubMed Central

Vigolo, Emilia; Hinze, Christian; Park, Joon-Keun; Roël, Giulietta; Balogh, András; Choi, Mira; Wübken, Anne; Cording, Jimmi; Blasig, Ingolf E.; Luft, Friedrich C.; Scheidereit, Claus; Schmidt-Ott, Kai M.; Schmidt-Ullrich, Ruth; Müller, Dominik N.

2016-01-01

NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type–specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)–induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed that IRI induced widespread NF-κB activation in renal tubular epithelia and in interstitial cells that peaked 2–3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBαΔN in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-κB–dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBαΔN-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-κB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response. PMID:26823548

Type 4 renal tubular acidosis in a kidney transplant recipient.

PubMed

Kulkarni, Manjunath

2016-02-01

We report a case of a 66-year-old diabetic patient who presented with muscle weakness 2 weeks after kidney transplantation. Her immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and steroids. She was found to have hyperkalemia and normal anion gap metabolic acidosis. Tacrolimus levels were in therapeutic range. All other drugs such as beta blockers and trimethoprim - sulfamethoxazole were stopped. She did not respond to routine antikalemic measures. Further evaluation revealed type 4 renal tubular acidosis. Serum potassium levels returned to normal after starting sodium bicarbonate and fludrocortisone therapy. Though hyperkalemia is common in kidney transplant recipients, determining exact cause can guide specific treatment. Copyright © 2016 Chang Gung University. Published by Elsevier B.V. All rights reserved.

Interobserver agreement for post mortem renal histopathology and diagnosis of acute tubular necrosis in critically ill patients.

PubMed

Glassford, Neil J; Skene, Alison; Guardiola, Maria B; Chan, Matthew J; Bagshaw, Sean M; Bellomo, Rinaldo; Solez, Kim

2017-12-01

The renal histopathology of critically ill patients dying with acute kidney injury (AKI) in intensive care units of high income countries remains uncertain. Retrospective observational assessment of interobserver agreement in the reporting of renal post mortem histopathology, and the ability of pathologists blinded to the clinical context to independently identify the presence of pre-mortem AKI from digital images of histological sections from 34 critically ill patients dying in teaching hospitals in Australia and Canada. We identified a heterogeneous cohort with a median age of 65 years (interquartile range [IQR], 56.5-77), APACHE II score of 27 (IQR, 19-33), and sepsis as the most common admission diagnosis (12/34; 35%). The most common proximate causes of death were cardiovascular (19/34; 56%) and respiratory (7/34; 21%) failure. AKI was common, with 23 patients (68%) developing RIFLE-F AKI, and 21 patients (62%) receiving renal replacement therapy. Structured reporting for tubular inflammation showed excellent agreement (kappa = 1), but no other subdomain demonstrated better than moderate agreement (kappa < 0.6). Only fair agreement (55.9% of cases; kappa = 0.23) was demonstrated on the diagnosis of moderate to severe acute tubular necrosis (ATN). Pathologist A predicted RIFLE-I or worse AKI with the diagnosis of ATN, with an overall accuracy of 61.8%; pathologist B predicted AKI with an accuracy of 35.3%. Post mortem assessment of the renal histopathology in critically ill patients is neither robust nor reproducible; independent pathologists agree poorly on the diagnosis of ATN, and their structural assessment appears dissociated from ante-mortem renal function.

Bmi-1 plays a critical role in the protection from acute tubular necrosis by mobilizing renal stem/progenitor cells.

PubMed

Lv, Xianhui; Yu, Zhenzhen; Xie, Chunfeng; Dai, Xiuliang; Li, Qing; Miao, Dengshun; Jin, Jianliang

2017-01-22

The regeneration of injured tubular cell occurs primarily from intrinsic renal stem/progenitor cells (RSCs) labeled with CD24 and CD133 after acute tubular necrosis (ATN). Bmi-1 plays a crucial role in regulating self-renewal, differentiation and aging of multiple adult stem cells and progenitor cells. Bmi-1 was rapidly elevated in the induction of adult kidney regeneration by renal injury. To determine whether Bmi-1 maintained mobilization of RSCs in the protection from ATN, glycerol-rhabdomyolysis-induced ATN were performed in wild type (WT) and Bmi-1-deficient (Bmi-1 -/- ) mice. Their ATN phenotypes were analyzed; CD24 and CD133 double positive (CD24 + CD133 + ) cells were measured; and the levels of serum urea nitrogen (SUN) and serum creatinine (SCr) were detected. We found that CD24 + CD133 + RSCs were mobilized in WT ATN mice with the increased expression of Bmi-1; Bmi-1 deficiency led to increased tubular cast formation and necrosis, elevated levels of SUN and SCr, decreased tubular proliferation, and immobilized ratio of RSCs in ATN. These findings indicated that Bmi-1 played a critical role in the protection from ATN by maintaining mobilization of RSCs and would be a novel therapeutic target for preventing the progression of ATN. Copyright © 2016 Elsevier Inc. All rights reserved.

Bmi-1 plays a critical role in the protection from acute tubular necrosis by mobilizing renal stem/progenitor cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lv, Xianhui; Yu, Zhenzhen; Xie, Chunfeng

The regeneration of injured tubular cell occurs primarily from intrinsic renal stem/progenitor cells (RSCs) labeled with CD24 and CD133 after acute tubular necrosis (ATN). Bmi-1 plays a crucial role in regulating self-renewal, differentiation and aging of multiple adult stem cells and progenitor cells. Bmi-1 was rapidly elevated in the induction of adult kidney regeneration by renal injury. To determine whether Bmi-1 maintained mobilization of RSCs in the protection from ATN, glycerol-rhabdomyolysis-induced ATN were performed in wild type (WT) and Bmi-1-deficient (Bmi-1{sup −/−}) mice. Their ATN phenotypes were analyzed; CD24 and CD133 double positive (CD24{sup +}CD133{sup +}) cells were measured; andmore » the levels of serum urea nitrogen (SUN) and serum creatinine (SCr) were detected. We found that CD24{sup +}CD133{sup +} RSCs were mobilized in WT ATN mice with the increased expression of Bmi-1; Bmi-1 deficiency led to increased tubular cast formation and necrosis, elevated levels of SUN and SCr, decreased tubular proliferation, and immobilized ratio of RSCs in ATN. These findings indicated that Bmi-1 played a critical role in the protection from ATN by maintaining mobilization of RSCs and would be a novel therapeutic target for preventing the progression of ATN.« less

Sjögren syndrome presenting with hypopotassemic periodic paralysis due to renal tubular acidosis

PubMed Central

Ataoglu, Esra Hayriye; Demir, Betul; Tuna, Mazhar; Çavus, Bilger; Cetin, Faik; Temiz, Levent Umit; Ozturk, Savas; Yenigun, Mustafa

2012-01-01

Summary Background: Sjögren syndrome (SS) is an autoimmune-lymphoproliferative disorder characterized by mononuclear cell infiltration of exocrine glands. Clinically, Sjögren syndrome (SS) has a wide spectrum, varying from autoimmune exocrinopathy to systemic involvement. There have been few cases reporting that primary SS developed with distal renal tubular acidosis clinically. Case Report: Here, we present a case with primary Sjögren syndrome accompanied by hypopotassemic paralysis due to renal tubular acidosis. Severe hypopotassemia, hyperchloremic metabolic acidosis, alkaline urine and disorder in urinary acidification test were observed in the biochemical examination of the 16-year-old female patient, who had applied to our clinic for extreme loss of muscle force. After the examinations it was determined that the patient had developed Type 1 RTA (distal RTA) due to primary Sjögren syndrome. Potassium and alkaline replacement was made and an immediate total recovery was achieved. Conclusions: Hypopotassemic paralysis due to primary Sjögren syndrome is a rare but severe disorder that could lead to death if not detected early and cured appropriately. Thus, effective treatment should be immediately initiated in cases where severe hypopotassemia is accompanied by metabolic acidosis, and the cases should also be examined for extraglandular involvement of SS. PMID:23569525

Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubular epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, J.-S.; Chuang, L.-Y.; Guh, J.-Y.

2008-12-01

Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE,more » or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27{sup Kip1}, collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells.« less

Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling.

PubMed

Wei, Xiaofan; Wang, Xiang; Xia, Yang; Tang, Yan; Li, Feng; Fang, Weigang; Zhang, Hongquan

2014-01-01

Kindlin-2 is an adaptor protein that contributes to renal tubulointerstitial fibrosis (TIF). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells was regarded as one of the key events in TIF. To determine whether kindlin-2 is involved in the EMT process, we investigated its regulation of EMT in human kidney tubular epithelial cells (TECs) and explored the underlying mechanism. In this study, we found that overexpression of kindlin-2 suppressed epithelial marker E-cadherin and increased the expression of fibronectin and the myofibroblast marker α-smooth muscle actin (SMA). Kindlin-2 significantly activated ERK1/2 and Akt, and inhibition of ERK1/2 or Akt reversed kindlin-2-induced EMT in human kidney TECs. Mechanistically, kindlin-2 interacted with Ras and son of sevenless (Sos)-1. Furthermore, overexpression of kindlin-2 increased Ras activation through recruiting Sos-1. Treatment with a Ras inhibitor markedly repressed kindlin-2-induced ERK1/2 and Akt activation, leading to restraint of EMT. We further demonstrated that knockdown of kindlin-2 inhibited EGF-induced Ras-Sos-1 interaction, resulting in reduction of Ras activation and suppression of EMT stimulated by EGF. Importantly, we found that depletion of kindlin-2 significantly inhibited activation of ERK1/2 and Akt signaling in mice with unilateral ureteral obstruction. We conclude that kindlin-2, through activating Ras and the downstream ERK1/2 and Akt signaling pathways, plays an important role in regulating renal tubular EMT and could be a potential therapeutic target for the treatment of fibrotic kidney diseases.

Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hasegawa, Kazuhiro; Wakino, Shu; Yoshioka, Kyoko

2008-07-18

NAD{sup +}-dependent protein deacetylase Sirt1 regulates cellular apoptosis. We examined the role of Sirt1 in renal tubular cell apoptosis by using HK-2 cells, proximal tubular cell lines with or without reactive oxygen species (ROS), H{sub 2}O{sub 2}. Without any ROS, Sirt1 inhibitors enhanced apoptosis and the expression of ROS scavenger, catalase, and Sirt1 overexpression downregulated catalase. When apoptosis was induced with H{sub 2}O{sub 2}, Sirt1 was upregulated with the concomitant increase in catalase expression. Sirt1 overexpression rescued H{sub 2}O{sub 2}-induced apoptosis through the upregulation of catalase. H{sub 2}O{sub 2} induced the nuclear accumulation of forkhead transcription factor, FoxO3a and themore » gene silencing of FoxO3a enhanced H{sub 2}O{sub 2}-induced apoptosis. In conclusion, endogenous Sirt1 maintains cell survival by regulating catalase expression and by preventing the depletion of ROS required for cell survival. In contrast, excess ROS upregulates Sirt1, which activates FoxO3a and catalase leading to rescuing apoptosis. Thus, Sirt1 constitutes a determinant of renal tubular cell apoptosis by regulating cellular ROS levels.« less

Urinary cystatin C as a renal biomarker and its immunohistochemical localization in anti-GBM glomerulonephritis rats.

PubMed

Togashi, Yuko; Imura, Naoko; Miyamoto, Yohei

2013-11-01

The usefulness of urinary cystatin C for the early detection of renal damage in anti-glomerular basement membrane (GBM) glomerulonephritis rats was investigated and compared to other biomarkers (β2-microglobulin, calbindin, clusterin, epidermal growth factor (EGF), alpha-glutathione S-transferase (GST-α), mu-glutathione S-transferase (GST-μ), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin, tissue inhibitor of metalloprotease-1 (TIMP-1), and vascular endothelial growth factor (VEGF)). Urinary levels of cystatin C increased in anti-GBM glomerulonephritis rats, whereas the conventional markers, plasma creatinine and UN did not, demonstrating its usefulness for the early detection of renal damage associated with anti-GBM glomerulonephritis. As well as cystatin C, urinary β2-microglobulin, clusterin, GST-α, GST-μ, KIM-1, and NGAL also had the potential to detect renal damage associated with anti-GBM glomerulonephritis. Furthermore, the immunohistochemical localization of cystatin C in the kidney was examined. Cystatin C expression was mainly observed in the proximal renal tubules in anti-GBM glomerulonephritis rats, and its expression barely changed with the progression of glomerulonephritis. Cystatin C expression was also observed in the tubular lumen of the cortex and medulla when glomerulonephritis was marked, which was considered to be characteristic of renal damage. In conclusion, urinary cystatin C, β2-microglobulin, clusterin, GST-α, GST-μ, KIM-1, and NGAL could be useful biomarkers of renal damage in anti-GBM glomerulonephritis rats. Immunohistochemical cystatin C expression in the proximal renal tubules was barely changed by the progression of glomerulonephritis, but it was newly observed in the tubular lumen when renal damage was apparent. Crown Copyright © 2013. Published by Elsevier GmbH. All rights reserved.

Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scharpfenecker, Marion, E-mail: m.scharpfenecker@nki.nl; Floot, Ben; Russell, Nicola S.

Purpose: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. Methods and Materials: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, andmore » 40 weeks after irradiation. Results: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. Conclusions: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.« less

Renal damage detected by DMSA, despite normal renal ultrasound, in children with febrile UTI.

PubMed

Bush, N C; Keays, M; Adams, C; Mizener, K; Pritzker, K; Smith, W; Traylor, J; Villanueva, C; Snodgrass, W T

2015-06-01

2011 American Academy of Pediatrics guidelines recommended renal-bladder ultrasound (RBUS) as the only evaluation after febrile urinary tract infection (FUTI) in infants aged 2-24 months. We determined the sensitivity, specificity, and false negative rate of RBUS to identify DMSA-detected renal damage in this age group as well as in older children. Consecutive patients referred to pediatric urology with a history of FUTI underwent DMSA ≥ 3 months after FUTI. Abnormal RBUS was defined as: Society of Fetal Urology hydronephrosis grades I-IV; hydroureter ≥ 7 mm; renal scar defined as focal parenchymal thinning; and/or size discrepancy ≥ 1 cm between kidneys. Abnormal DMSA was presence of any focal uptake defects and/or split renal function < 44%. We calculated sensitivity, specificity, positive and negative predictive values, and false negative rates of RBUS compared to DMSA. 618 patients (79% female), median age 3.4 years, were referred for FUTIs. Of the 512 (83%) with normal RBUS, 99 (19%) had abnormal DMSA. Children with normal RBUS after their first FUTI had abnormal DMSA in 15/151 (10%) aged ≤ 24 months and 23/119 (19%) aged > 24 months. RBUS had poor sensitivity (34%) and low positive predictive value (47%) to identify patients with renal damage. 99/149 (66%) children with renal damage on DMSA had normal RBUS. After FUTI, 66% of children with reduced renal function and/or renal cortical defects found by DMSA scintigraphy had a normal RBUS. Since abnormal DMSA may correlate with increased risk for VUR, recurrent FUTI and renal damage, our data suggest RBUS alone will fail to detect a significant proportion of patients at risk. The data suggest that imaging after FUTI should include acute RBUS and delayed DMSA, reserving VCUG for patients with abnormal DMSA and/or recurrent FUTI. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Primary hyperparathyroidism and proximal renal tubular acidosis: Report of two cases

PubMed Central

Siddiqui, Abdullah A.; Wilson, Douglas R.

1972-01-01

Two cases of primary hyperparathyroidism due to single parathyroid adenomas presented with the additional feature of hyperchloremic acidosis. The defect in urinary acidification responsible was not of the distal or gradient-limited type since both patients could lower urine pH adequately. However, there was a defect of bicarbonate reabsorption, an abnormality referred to as the proximal or rate-limited type of renal tubular acidosis. It is suggested that this defect represents an exaggeration of the physiological effect of parathormone on bicarbonate reabsorption and may be responsible for the frequent finding of hyperchloremia in association with primary hyperparathyroidism as well as for the urinary bicarbonate-wasting associated with a variety of causes of secondary hyperparathyroidism. PMID:5012229

Apelin attenuates TGF-β1-induced epithelial to mesenchymal transition via activation of PKC-ε in human renal tubular epithelial cells.

PubMed

Wang, Li-Yan; Diao, Zong-Li; Zheng, Jun-Fang; Wu, Yi-Ru; Zhang, Qi-Dong; Liu, Wen-Hu

2017-10-01

Epithelial to mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of renal fibrosis. Apelin, a bioactive peptide, has recently been recognized to protect against renal profibrotic activity, but the underlying mechanism has not yet been elucidated. In this study, we investigated the regulation of EMT in the presence of apelin-13 in vitro. Expression of the mesenchymal marker alpha-smooth muscle actin (α-SMA) and the epithelial marker E-cadherin was examined by immunofluorescence and western blotting in transforming growth factor beta 1 (TGF-β1)-stimulated human proximal tubular epithelial cells. Expression of extracellular matrix, fibronectin and collagen-I was examined by quantitative real-time PCR and ELISA. F13A, an antagonist of the apelin receptor APJ, and small interfering RNA targeting protein kinase C epsilon (PKC-ε) were used to explore the relevant signaling pathways. Apelin attenuated TGF-β1-induced EMT, and inhibited the EMT-associated increase in α-SMA, loss of E-cadherin, and secretion of extracellular matrix. Moreover, apelin activated PKC-ε in tubular epithelial cells, which in turn decreased phospho-Smad2/3 levels and increased Smad-7 levels. APJ inhibition or PKC-ε deletion diminished apelin-induced modulation of Smad signaling and suppression of tubular EMT. Our findings identify a novel PKC-ε-dependent mechanism in which apelin suppresses TGF-β1-mediated activation of Smad signaling pathways and thereby inhibits tubular EMT. These results suggest that apelin may be a new agent that can suppress renal fibrosis and retard chronic kidney disease progression. Copyright © 2017 Elsevier Inc. All rights reserved.

Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome.

PubMed

El Ati, Zohra; Fatma, Lilia Ben; Boulahya, Ghada; Rais, Lamia; Krid, Madiha; Smaoui, Wided; Maiz, Hedi Ben; Beji, Soumaya; Zouaghi, Karim; Moussa, Fatma Ben

2014-09-01

Renal involvement in Sjogren's syndrome (SS) is not uncommon and may precede other complaints. Tubulointerstitial nephritis is the most common renal disease in SS and may lead to renal tubular acidosis (RTA), which in turn may cause osteomalacia. Nevertheless, osteomalacia rarely occurs as the first manifestation of a renal tubule disorder due to SS. We herewith describe a 43-year-old woman who was admitted to our hospital for weakness, lumbago and inability to walk. X-ray of the long bones showed extensive demineralization of the bones. Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis (chlorine: 114 mmol/L; alkaline reserve: 14 mmol/L). The serum alkaline phosphatase levels were elevated. The serum levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D were low and borderline low, respectively, and the parathyroid hormone level was 70 pg/L. Urinalysis showed inappropriate alkaline urine (urinary PH: 7), glycosuria with normal blood glucose, phosphaturia and uricosuria. These values indicated the presence of both distal and proximal RTA. Our patient reported dryness of the mouth and eyes and Schirmer's test showed xerophthalmia. An accessory salivary gland biopsy showed changes corresponding to stage IV of Chisholm and Masson score. Kidney biopsy showed diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates. Sicca syndrome and renal interstitial infiltrates indicated SS as the underlying cause of the RTA and osteomalacia. The patient received alkalinization, vitamin D (Sterogyl ®), calcium supplements and steroids in an initial dose of 1 mg/kg/day, tapered to 10 mg daily. The prognosis was favorable and the serum creatinine level was 1.7 mg/dL, calcium was 2.2 mmol/L and serum phosphate was 0.9 mmol/L.

βENaC acts as a mechanosensor in renal vascular smooth muscle cells that contributes to renal myogenic blood flow regulation, protection from renal injury and hypertension.

PubMed

Drummond, Heather A; Stec, David E

2015-06-01

Pressure-induced constriction (also known as the "myogenic response") is an important mechanodependent response in small renal arteries and arterioles. The response is initiated by vascular smooth muscle cell (VSMC) stretch due to an increase in intraluminal pressure and leads to vasoconstriction. The myogenic response has two important roles as a mechanism of local blood flow autoregulation and protection against systemic blood pressure-induced microvascular damage. However, the molecular mechanisms underlying initiation of myogenic response are unresolved. Although several molecules have been considered initiators of the response, our laboratory has focused on the role of degenerin proteins because of their strong evolutionary link to mechanosensing in the nematode. Our laboratory has addressed the hypothesis that certain degenerin proteins act as mechanosensors in VSMCs. This article discusses the importance of a specific degenerin protein, β Epithelial Na + Channel (βENaC), in pressure-induced vasoconstriction, renal blood flow and susceptibility to renal injury. We propose that loss of the renal myogenic constrictor response delays the correction of renal blood flow that occurs with fluctuations in systemic pressure, which allows pressure swings to be transmitted to the microvasculature, thus increasing the susceptibility to renal injury and hypertension. The role of βENaC in myogenic regulation is independent of tubular βENaC and thus represents a non-tubular role for βENaC in renal-cardiovascular homeostasis.

Autophagy activation protects shock wave induced renal tubular epithelial cell apoptosis may through modulation of Akt/ GSK-3β pathway.

PubMed

Long, Qingzhi; Li, Xiang; He, Hui; He, Dalin

2016-01-01

Extracorporeal shock wave lithotripsy (ESWL) is well documented to exert destructive effect to renal cells and its mechanism is not clear. Autophagy is one of cell basic response for stressful conditions and it is important to determine cell's fate. The aim of this study is to elucidate the role of autophagy in the process of shock wave-induced renal cells injury. NRK-52E cell, a rat renal tubular epithelial cell, was exposed to shock wave at the voltage of 14KV. GFP-LC3 puncta was used to monitor Autophagy flux in the process of shock wave injury. Autophagic relative proteins, such as light chain 3 (LC3), beclin-1 and p62, were also examined. Cell variability and apoptosis were detected when inhibition autophagy with 3-methyladenine (3MA) or stimulating its activity with rapamycin during the process of shock wave injury. The role of Akt/ GSK-3β and its connection with autophagy in the process of shock wave injury were also investigated. Shock wave was confirmed to activate autophagy in renal cells, which was manifested in LC3-II turnover, beclin-1 induction and degradation of p62. Inhibition autophagy enhanced cell damage or apoptosis, whereas its stimulating was able to exert protection from shock wave injury. Akt/ GSK-3β, a cell-survival signaling pathway, can also be activated during the process. And its activation could be suppressed by blockade autophagy. Autophagy is a self-protective response for renal cells from shock wave injury. The cyto-protection of autophagy may be connected with modulation Akt/ GSK-3β pathway.

Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling.

PubMed

Tan, Xiao-Hua; Zheng, Xiao-Meng; Yu, Li-Xia; He, Jian; Zhu, Hong-Mei; Ge, Xiu-Ping; Ren, Xiao-Li; Ye, Fa-Qing; Bellusci, Saverio; Xiao, Jian; Li, Xiao-Kun; Zhang, Jin-San

2017-11-01

Ischaemia-reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI-induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R-induced acute renal dysfunction and largely blunted I/R-induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL-positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro-apoptotic alteration of Bcl2/Bax expression, caspase-3 activation, loss of mitochondrial membrane potential and K ATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the K ATP channel blocker 5-HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post-I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage-associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL-1α, IL-6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1-mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI-induced AKI. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Ultrastructural study of electron dense deposits in renal tubular basement membrane: prevalence and relationship to epithelial atrophy.

PubMed

Yong, Jim L C; Killingsworth, Murray C

2014-08-01

This study reports the prevalence of immune deposits associated with the proximal and distal tubules in a series of routine renal biopsies received in our department during a single calendar year. From 87 cases, 65 (74%) were found to have glomerular immune deposits by immunofluorescence. Tubular immune deposits were found in 12 cases (18%), 3 of which had no glomerular deposits. By transmission electron microscopy (EM), 58 cases (66%) were found to have deposits of granular or vesicular material associated with the tubular basement membranes (TBM). Finely granular electron dense deposits appeared to correspond to the immune deposits seen by immunofluorescence microscopy (IF) and may be a sensitive marker of immune deposition.

Ultrastructural Study of Electron Dense Deposits in Renal Tubular Basement Membrane: Prevalence and Relationship to Epithelial Atrophy

PubMed Central

Killingsworth, Murray C.

2014-01-01

This study reports the prevalence of immune deposits associated with the proximal and distal tubules in a series of routine renal biopsies received in our department during a single calendar year. From 87 cases, 65 (74%) were found to have glomerular immune deposits by immunofluorescence. Tubular immune deposits were found in 12 cases (18%), 3 of which had no glomerular deposits. By transmission electron microscopy (EM), 58 cases (66%) were found to have deposits of granular or vesicular material associated with the tubular basement membranes (TBM). Finely granular electron dense deposits appeared to correspond to the immune deposits seen by immunofluorescence microscopy (IF) and may be a sensitive marker of immune deposition. PMID:24933115

Hemodynamic and tubular changes induced by contrast media.

PubMed

Caiazza, Antonella; Russo, Luigi; Sabbatini, Massimo; Russo, Domenico

2014-01-01

The incidence of acute kidney injury induced by contrast media (CI-AKI) is the third cause of AKI in hospitalized patients. Contrast media cause relevant alterations both in renal hemodynamics and in renal tubular cell function that lead to CI-AKI. The vasoconstriction of intrarenal vasculature is the main hemodynamic change induced by contrast media; the vasoconstriction is accompanied by a cascade of events leading to ischemia and reduction of glomerular filtration rate. Cytotoxicity of contrast media causes apoptosis of tubular cells with consequent formation of casts and worsening of ischemia. There is an interplay between the negative effects of contrast media on renal hemodynamics and on tubular cell function that leads to activation of renin-angiotensin system and increased production of reactive oxygen species (ROS) within the kidney. Production of ROS intensifies cellular hypoxia through endothelial dysfunction and alteration of mechanisms regulating tubular cells transport. The physiochemical characteristics of contrast media play a critical role in the incidence of CI-AKI. Guidelines suggest the use of either isoosmolar or low-osmolar contrast media rather than high-osmolar contrast media particularly in patients at increased risk of CI-AKI. Older age, presence of atherosclerosis, congestive heart failure, chronic renal disease, nephrotoxic drugs, and diuretics may multiply the risk of CI-AKI.

Hemodynamic and Tubular Changes Induced by Contrast Media

PubMed Central

Caiazza, Antonella; Russo, Luigi; Russo, Domenico

2014-01-01

The incidence of acute kidney injury induced by contrast media (CI-AKI) is the third cause of AKI in hospitalized patients. Contrast media cause relevant alterations both in renal hemodynamics and in renal tubular cell function that lead to CI-AKI. The vasoconstriction of intrarenal vasculature is the main hemodynamic change induced by contrast media; the vasoconstriction is accompanied by a cascade of events leading to ischemia and reduction of glomerular filtration rate. Cytotoxicity of contrast media causes apoptosis of tubular cells with consequent formation of casts and worsening of ischemia. There is an interplay between the negative effects of contrast media on renal hemodynamics and on tubular cell function that leads to activation of renin-angiotensin system and increased production of reactive oxygen species (ROS) within the kidney. Production of ROS intensifies cellular hypoxia through endothelial dysfunction and alteration of mechanisms regulating tubular cells transport. The physiochemical characteristics of contrast media play a critical role in the incidence of CI-AKI. Guidelines suggest the use of either isoosmolar or low-osmolar contrast media rather than high-osmolar contrast media particularly in patients at increased risk of CI-AKI. Older age, presence of atherosclerosis, congestive heart failure, chronic renal disease, nephrotoxic drugs, and diuretics may multiply the risk of CI-AKI. PMID:24678510

The subtype of alpha-adrenoceptor involved in the neural control of renal tubular sodium reabsorption in the rabbit.

PubMed Central

Hesse, I F; Johns, E J

1984-01-01

A study was undertaken in pentobarbitone anaesthetized rabbits, undergoing a saline diuresis, to determine the subtype of alpha-adrenoceptor mediating renal tubular sodium reabsorption. Stimulation of the renal nerves at low rates, to cause an 11% fall in renal blood flow, did not change glomerular filtration rate but significantly reduced urine flow rate, and absolute and fractional sodium excretions by approximately 40%. These responses were reproducible in different groups of animals and with time. Renal nerve stimulation during an intra-renal arterial infusion of prazosin, to block alpha 1-adrenoceptors, had no effect on the renal haemodynamic response but completely abolished the reductions in urine flow rate, and absolute and fractional sodium excretion. During intra-renal arterial infusion of yohimbine, to block renal alpha 2-adrenoceptors, stimulation of the renal nerves to cause similar renal haemodynamic changes resulted in significantly larger reductions in urine flow rate, and absolute and fractional sodium excretion of about 52-58%. These results indicate that in the rabbit alpha 1-adrenoceptors are present on the renal tubules, which mediate the increase in sodium reabsorption caused by renal nerve stimulation. They further suggest the presence of presynaptic alpha 2-adrenoceptors on those nerves innervating the renal tubules. PMID:6086915

DNA Damage Response in Cisplatin-Induced Nephrotoxicity

PubMed Central

Zhu, Shiyao; Pabla, Navjotsingh; Tang, Chengyuan; He, Liyu; Dong, Zheng

2015-01-01

Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side-effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and death, resulting in acute kidney injury (AKI). Recent studies have suggested that DNA damage and the associated DNA damage response (DDR) is an important pathogenic mechanism of AKI following cisplatin treatment. Activation of DDR may lead to cell cycle arrest and DNA repair for cell survival or, in the presence of severe injury, kidney cell death. Modulation of DDR may provide novel renoprotective strategies for cancer patients undergoing cisplatin chemotherapy. PMID:26564230

Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage

PubMed Central

Habib, Samy L.; Yadav, Anamika; Kidane, Dawit; Weiss, Robert H.; Liang, Sitai

2016-01-01

ABSTRACT Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser792 and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy. PMID:27611085

ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice

PubMed Central

Jones, Frances E.; Bailey, Matthew A.; Murray, Lydia S.; Lu, Yinhui; McNeilly, Sarah; Schlötzer-Schrehardt, Ursula; Lennon, Rachel; Sado, Yoshikazu; Brownstein, David G.; Mullins, John J.; Kadler, Karl E.; Van Agtmael, Tom

2016-01-01

ABSTRACT Collagen IV is a major component of basement membranes, and mutations in COL4A1, which encodes collagen IV alpha chain 1, cause a multisystemic disease encompassing cerebrovascular, eye and kidney defects. However, COL4A1 renal disease remains poorly characterized and its pathomolecular mechanisms are unknown. We show that Col4a1 mutations in mice cause hypotension and renal disease, including proteinuria and defects in Bowman's capsule and the glomerular basement membrane, indicating a role for Col4a1 in glomerular filtration. Impaired sodium reabsorption in the loop of Henle and distal nephron despite elevated aldosterone levels indicates that tubular defects contribute to the hypotension, highlighting a novel role for the basement membrane in vascular homeostasis by modulation of the tubular response to aldosterone. Col4a1 mutations also cause diabetes insipidus, whereby the tubular defects lead to polyuria associated with medullary atrophy and a subsequent reduction in the ability to upregulate aquaporin 2 and concentrate urine. Moreover, haematuria, haemorrhage and vascular basement membrane defects confirm an important vascular component. Interestingly, although structural and compositional basement membrane defects occurred in the glomerulus and Bowman's capsule, no tubular basement membrane defects were detected. By contrast, medullary atrophy was associated with chronic ER stress, providing evidence for cell-type-dependent molecular mechanisms of Col4a1 mutations. These data show that both basement membrane defects and ER stress contribute to Col4a1 renal disease, which has important implications for the development of treatment strategies for collagenopathies. PMID:26839400

[Effect of the chelator BPCBG on the decorporation of uranium in vivo and uranium-induced damage of human renal tubular epithelial cells in vitro].

PubMed

Bao, Yi-zhong; Wang, Dan; Hu, Yu-xing; Xu, Ai-hong; Sun, Mei-zhen; Chen, Hong-hong

2011-11-01

This study is to assess the efficacy of BPCBG on the decorporation of uranium (VI) and protecting human renal proximal tubular epithelial cells (HK-2) against uranium-induced damage. BPCBG at different doses was injected intramuscularly to male SD rats immediately after a single intraperitoneal injection of UO2(CH3COO)2. Twenty-four hours later uranium contents in urine, kidneys and femurs were measured by ICP-MS. After HK-2 cells were exposed to UO2(CH3COO)2 immediately or for 24 h followed by BPCBG treatment at different doses for another 24 or 48 h, the uranium contents in HK-2 cells were measured by ICP-MS, the cell survival was assayed by cell counting kit-8 assay, formation of micronuclei was determined by the cytokinesis-block (CB) micronucleus assay and the production of intracellular reactive oxygen species (ROS) was detected by 2',7'-dichlorofluorescin diacetate (DCFH-DA) oxidation. DTPA-CaNa3 was used as control. It was found that BPCBG at dosages of 60, 120, and 600 micromol kg(-1) resulted in 37%-61% increase in 24 h-urinary uranium excretion, and significantly decreased the amount of uranium retention in kidney and bone to 41%-31% and 86%-42% of uranium-treated group, respectively. After HK-2 cells that had been pre-treated with UO2(CH3COO)2 for 24 h were treated with the chelators for another 24 h, 55%-60% of the intracellular uranium was removed by 10-250 micromol L(-1) of BPCBG. Treatment of uranium-treated HK-2 cells with BPCBG significantly enhanced the cell survival, decreased the formation of micronuclei and inhibited the production of intracellular ROS. Although DTPA-CaNa3 markedly reduced the uranium retention in kidney of rats and HK-2 cells, its efficacy of uranium removal from body was significantly lower than that of BPCBG and it could not protect uranium-induced cell damage. It can be concluded that BPCBG effectively decorporated the uranium from UO2(CH3COO)2-treated rats and HK-2 cells, which was better than DTPA-CaNa3. It could also

Freezing/Thawing without Cryoprotectant Damages Native but not Decellularized Porcine Renal Tissue

PubMed Central

Poornejad, Nafiseh; Frost, Timothy S; Scott, Daniel R; Elton, Brinden B; Reynolds, Paul R; Roeder, Beverly L; Cook, Alonzo D

2015-01-01

abstract Whole organ decellularization of porcine renal tissue and recellularization with a patient's own cells would potentially overcome immunorejection, which is one of the most significant problems with allogeneic kidney transplantation. However, there are obstacles to achieving this goal, including preservation of the decellularized extracellular matrix (ECM), identifying the proper cell types, and repopulating the ECM before transplantation. Freezing biological tissue is the best option to avoid spoilage; however, it may damage the structure of the tissue or disrupt cellular membranes through ice crystal formation. Cryoprotectants have been used to repress ice formation during freezing, although cell toxicity can still occur. The effect of freezing/thawing on native (n = 10) and decellularized (n = 10) whole porcine kidneys was studied without using cryoprotectants. Results showed that the elastic modulus of native kidneys was reduced by a factor of 22 (P < 0.0001) by freezing/thawing or decellularization, while the elastic modulus for decellularized ECM was essentially unchanged by the freezing/thawing process (p = 0.0636). Arterial pressure, representative of structural integrity, was also reduced by a factor of 52 (P < 0.0001) after freezing/thawing for native kidneys, compared to a factor of 43 (P < 0.0001) for decellularization and a factor of 4 (P < 0.0001) for freezing/thawing decellularized structures. Both freezing/thawing and decellularization reduced stiffness, but the reductions were not additive. Investigation of the microstructure of frozen/thawed native and decellularized renal tissues showed increased porosity due to cell removal and ice crystal formation. Orcein and Sirius staining showed partial damage to elastic and collagen fibers after freezing/thawing. It was concluded that cellular damage and removal was more responsible for reducing stiffness than fibril destruction. Cell viability and growth were demonstrated on decellularized frozen

Evaluation of the potential interaction between tofacitinib and drugs that undergo renal tubular secretion using metformin, an in vivo marker of renal organic cation transporter 2.

PubMed

Klamerus, Karen J; Alvey, Christine; Li, Lei; Feng, Bo; Wang, Rong; Kaplan, Irina; Shi, Haihong; Dowty, Martin E; Krishnaswami, Sriram

2014-11-01

Tofacitinib is a novel, oral Janus kinase inhibitor. The potential for drug-drug interactions (DDIs) between tofacitinib and drugs that undergo renal tubular secretion was evaluated using metformin as a probe transporter substrate, and genotyping for organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion 1 polymorphisms. Twenty-four healthy male subjects completed this open-label, fixed-sequence study. Subjects were administered a single oral metformin 500 mg dose on Days 1 and 4, and multiple oral tofacitinib 30 mg twice daily doses on Days 2, 3, and 4. Subjects underwent serial blood and urine samplings (Days 1 and 4) to estimate metformin pharmacokinetics. A single blood sample for tofacitinib was collected 2 hours after the morning dose (Day 4). The 90% confidence intervals for the ratios of maximum plasma concentration, area under the curve and renal clearance of metformin, with and without tofacitinib, were contained within the 80-125% acceptance range commonly used to establish a lack of DDI. No deaths, serious adverse events (AEs), severe AEs or discontinuations due to AEs were reported. The study confirms tofacitinib is unlikely to impact the pharmacokinetics of drugs that undergo renal tubular secretion, and concurs with its weak in vitro OCT2 inhibitory profile. © 2014, The American College of Clinical Pharmacology.

[Protective effect of Angelica sinensis polysaccharides on subacute renal damages induced by D-galactose in mice and its mechanism].

PubMed

Fan, Yan-ling; Xia, Jie-yu; Jia, Dao-yong; Zhang, Meng-si; Zhang, Yan-yan; Wang, Lu; Huang, Guo-ning; Wang, Ya-ping

2015-11-01

To explore the protective effect of Angelica sinensis polysaccharides(ASP) on subacute renal damages induced by D-galactose in mice and its mechanism. Male C57BL/6J mice were randomly divided into 3 groups, with 10 mice in each group. The D-galactose model group was subcutaneously injected with D-galactose (120 mg x kg(-1)), qd x 42; the ASP + D-galactose model group was intraperitoneally injected with ASP since the 8th day of the replication of the D-galactose model, qd x 35; and the normal control group was subcutaneously injected with saline at the same dose and time. On the 2nd day of after the injection, the peripheral blood was collected to measure the content of BUN, Crea, UA, Cys-C; paraffin sections were made to observe the renal histomorphology by HE staining; senescence-associated β-g-alactosidase (SA-β-Gal) stain was used to observe the relative optical density (ROD) in renal tissues; transmission electron microscopy was assayed to observe the renal ultrastructure; the renal tissue homogenate was prepared to measure the content of SOD, GSH-PX, MDA; the content of AGEs and 8-OH-dG were measured by ELISA. According to the result, compared with the D-galactose model group, the ASP + D-galactose model group showed obviously decreases in the content of BUN, Crea, UA, Cysc, AGES, 8-OH-dG, the number of hardening renal corpuscle, renal capsular space and renal tubular lumen, ROD of SA-β-Gal staining positive kidney cells, mesangial cells, basement membrane thickness, podocyte secondary processes fusion and MDA and increases in the number of normal renal corpuscle, ribosome and rough endoplasmic reticulum in podocytes, the activity of SOD and GSH-PX. In Conclusion, A. sinensis polysaccharides can antagonize kidney subacute damages induced by D-galactose in mice. Its protective mechanism may be correlated with the inhibition of the oxidative stress injury.

Renal Oxidative Stress Induced by Long-Term Hyperuricemia Alters Mitochondrial Function and Maintains Systemic Hypertension

PubMed Central

Cristóbal-García, Magdalena; García-Arroyo, Fernando E.; Arellano-Buendía, Abraham S.; Madero, Magdalena; Rodríguez-Iturbe, Bernardo; Pedraza-Chaverrí, José; Zazueta, Cecilia; Johnson, Richard J.; Sánchez Lozada, Laura-Gabriela

2015-01-01

We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. PMID:25918583

Downregulation of cell survival signalling pathways and increased cell damage in hydrogen peroxide-treated human renal proximal tubular cells by alpha-erythropoietin.

PubMed

Andreucci, M; Fuiano, G; Presta, P; Lucisano, G; Leone, F; Fuiano, L; Bisesti, V; Esposito, P; Russo, D; Memoli, B; Faga, T; Michael, A

2009-08-01

Erythropoietin has been shown to have a protective effect in certain models of ischaemia-reperfusion, and in some cases the protection has been correlated with activation of signalling pathways known to play a role in cell survival and proliferation. We have studied whether erythropoietin would overcome direct toxic effects of hydrogen peroxide (H(2)O(2)) treatment to human renal proximal tubular (HK-2) cells. HK-2 cells were incubated with H(2)O(2) (2 mm) for 2 h with or without erythropoietin at concentrations of 100 and 400 U/ml, and cell viability/proliferation was assessed by chemical reduction of MTT. Changes in phosphorylation state of the kinases Akt, glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) were also analysed. Cells incubated with H(2)O(2) alone showed a significant decrease in viability, which did not significantly change by addition of erythropoietin at concentration of 100 U/ml, but was further reduced when concentration of erythropoietin was increased to 400 U/ml. Phosphorylation state of the kinases Akt, GSK-3beta, mTOR and ERK1/ERK2 of H(2)O(2)-treated HK-2 cells was slightly altered in the presence of erythropoietin at concentration of 100 U/ml, but was significantly less in the presence of erythropoietin at a concentration of 400 U/ml. Phosphorylation of forkhead transcription factor FKHRL1 was diminished in cells incubated with H(2)O(2) and erythropoietin at a concentration of 400 U/ml. Erythropoietin, at high concentrations, may significantly increase cellular damage in HK-2 cells subjected to oxidative stress, which may be due in part to decrease in activation of important signalling pathways involved in cell survival and/or cell proliferation.

Renal uptake and tolerability of a 2'-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey.

PubMed

Henry, Scott P; Johnson, Mark; Zanardi, Thomas A; Fey, Robert; Auyeung, Diana; Lappin, Patrick B; Levin, Arthur A

2012-11-15

The primary target organ for uptake of systemically administered phosphorothioate oligonucleotides is the kidney cortex and the proximal tubular epithelium in particular. To determine the effect of oligonucleotide uptake on renal function, a detailed renal physiology study was performed in cynomolgus monkeys treated with 10-40 mg/kg/week ISIS 113715 for 4 weeks. The concentrations of oligonucleotide in the kidney cortex ranged from 1400 to 2600 μg/g. These concentrations were associated with histologic changes in proximal tubular epithelial cells that ranged from the appearance of cytoplasmic basophilic granules to atrophic and degenerative changes at higher concentrations. However, there were no renal functional abnormalities as determined by the typical measurements of blood urea nitrogen, serum creatinine, creatinine clearance, or urine specific gravity. Nor were there changes in glomerular filtration rate, or renal blood flow. Specific urinary markers of tubular epithelial cell damage, such as N-acetyl-glucosaminidase, and α-glutathione-s-transferase were not affected. Tubular function was further evaluated by monitoring the urinary excretion of amino acids, β(2)-microglobulin, or glucose. Renal function was challenged by administering a glucose load and by examining concentrating ability after a 4-h water deprivation. Neither challenge produced any evidence of change in renal function. The only change observed was a low incidence of increased urine protein/creatinine ratio in monkeys treated with ≥40 mg/kg/week which was rapidly reversible. Collectively, these data indicate that ISIS 113715-uptake by the proximal tubular epithelium has little or no effect on renal function at concentrations of 2600 μg/g. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Naproxen-induced Ca2+ movement and death in MDCK canine renal tubular cells.

PubMed

Cheng, H-H; Chou, C-T; Sun, T-K; Liang, W-Z; Cheng, J-S; Chang, H-T; Tseng, H-W; Kuo, C-C; Chen, F-A; Kuo, D-H; Shieh, P; Jan, C-R

2015-11-01

Naproxen is an anti-inflammatory drug that affects cellular calcium ion (Ca(2+)) homeostasis and viability in different cells. This study explored the effect of naproxen on [Ca(2+)](i) and viability in Madin-Darby canine kidney cells (MDCK) canine renal tubular cells. At concentrations between 50 μM and 300 μM, naproxen induced [Ca(2+)](i) rises in a concentration-dependent manner. This Ca(2+) signal was reduced partly when extracellular Ca(2+) was removed. The Ca(2+) signal was inhibited by a Ca(2+) channel blocker nifedipine but not by store-operated Ca(2+) channel inhibitors (econazole and SKF96365), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate, and a PKC inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with 2,5-di-tert-butylhydroquinone or thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+) pumps, partly inhibited naproxen-induced Ca(2+) signal. Inhibition of phospholipase C with U73122 did not alter naproxen-evoked [Ca(2+)](i) rises. At concentrations between 15 μM and 30 μM, naproxen killed cells in a concentration-dependent manner, which was not reversed by prechelating cytosolic Ca(2+) with the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl. Annexin V/propidium iodide staining data suggest that naproxen induced apoptosis. Together, in MDCK renal tubular cells, naproxen induced [Ca(2+)](i) rises by inducing Ca(2+) release from multiple stores that included the endoplasmic reticulum and Ca(2+) entry via nifedipine-sensitive Ca(2+) channels. Naproxen induced cell death that involved apoptosis. © The Author(s) 2015.

Effect of diuretics on renal tubular transport of calcium and magnesium.

PubMed

Alexander, R Todd; Dimke, Henrik

2017-06-01

Calcium (Ca 2+ ) and Magnesium (Mg 2+ ) reabsorption along the renal tubule is dependent on distinct trans- and paracellular pathways. Our understanding of the molecular machinery involved is increasing. Ca 2+ and Mg 2+ reclamation in kidney is dependent on a diverse array of proteins, which are important for both forming divalent cation-permeable pores and channels, but also for generating the necessary driving forces for Ca 2+ and Mg 2+ transport. Alterations in these molecular constituents can have profound effects on tubular Ca 2+ and Mg 2+ handling. Diuretics are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate sodium (Na + ) transport, but also indirectly affect renal Ca 2+ and Mg 2+ handling, i.e., by establishing a prerequisite electrochemical gradient. It is therefore not surprising that substantial alterations in divalent cation handling can be observed following diuretic treatment. The effects of diuretics on renal Ca 2+ and Mg 2+ handling are reviewed in the context of the present understanding of basal molecular mechanisms of Ca 2+ and Mg 2+ transport. Acetazolamide, osmotic diuretics, Na + /H + exchanger (NHE3) inhibitors, and antidiabetic Na + /glucose cotransporter type 2 (SGLT) blocking compounds, target the proximal tubule, where paracellular Ca 2+ transport predominates. Loop diuretics and renal outer medullary K + (ROMK) inhibitors block thick ascending limb transport, a segment with significant paracellular Ca 2+ and Mg 2+ transport. Thiazides target the distal convoluted tubule; however, their effect on divalent cation transport is not limited to that segment. Finally, potassium-sparing diuretics, which inhibit electrogenic Na + transport at distal sites, can also affect divalent cation transport. Copyright © 2017 the American Physiological Society.

[Case of young woman with Graves' disease and incomplete distal renal tubular acidosis with severe progress and cardiac arrest].

PubMed

Klimm, Wojciech; Kade, Grzegorz; Spaleniak, Sebastian; Dubchak, Ivanna; Niemczyk, Stanisław

2014-07-01

Diagnostic of renal tubular disorders can be often difficult. Incomplete form of distal Renal Tubular Acidosis (dRta) in course of Graves' disease was de novo recognized in a young woman hospitalized with a deep deficiency of potassium in blood serum complicated with cardiac arrest. Series of tests assessing the types and severity of water-electrolyte, acid-base and thyroid disorders were performed during a complex diagnosis. During the treatment of acute phase of the disease we intensified efforts to maintain basic life functions and to eliminate deep water-electrolyte disturbances. In the second phase of the treatment we determined an underlying cause of the disease, recognized dRTA, and introduced a specific long-term electrolyte and hormonal therapy. To confirm the diagnosis oral test with ammonium chloride (Wrong-Davies' test) was performed. After completion of the diagnostic and therapeutic process, the patient was included in the nephrological supervision on an outpatient basis. The basic drug for the therapy was sodium citrate. After a year of observation and continuing treatment we evaluated therapeutic results as good and permanent.

Renal function assessment in heart failure.

PubMed

Pérez Calvo, J I; Josa Laorden, C; Giménez López, I

Renal function is one of the most consistent prognostic determinants in heart failure. The prognostic information it provides is independent of the ejection fraction and functional status. This article reviews the various renal function assessment measures, with special emphasis on the fact that the patient's clinical situation and response to the heart failure treatment should be considered for the correct interpretation of the results. Finally, we review the literature on the performance of tubular damage biomarkers. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Systemic lupus erythematosus with Sjögren's syndrome and renal tubular acidosis presenting as nephrogenic diabetes insipidus.

PubMed

Parrey, Ashaq Hussain; Ahmad, Fayaz; Ahmad, Mushtaq; Basher, Adil

2018-01-01

Systemic lupus erythematosus (SLE) presenting as diabetes insipidus (DI) is a rare association; there is a case report of neurogenic DI in patients of SLE; however, SLE and nephrogenic DI has not been reported in literature. We present a case of SLE presenting as nephrogenic DI. We report a case who presented with DI (nephrogenic) and fulfilled criteria for SLE and Sjögren's syndrome with renal tubular acidosis.

[Study on the assay of proximal tubular antigen in urine and serum with an anti-human renal monoclonal antibody].

PubMed

Taniai, K

1991-10-01

Monoclonal antibodies (Mabs) were produced by immunizing mice with human kidney microsomal antigen. Mab-B1 recognized brushborder (B1-Ag) in proximal tubules. Using Mab-B1, B1-Ag was assayed in the urine and serum of renal disease patients by sandwich ELISA. The subjects included normal control (Nor), minimal change nephrotic syndrome (MCNS), IgA nephropathy (IgA), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), and chronic renal failure (CRF) (s-Cr greater than 2 mg/dl). Urinary B1-Ag demonstrated significant increases in the IgA (p less than 0.001), MN (p less than 0.001), MPGN (p less than 0.001) and CRF (p less than 0.01) groups as compared to the Nor group. There was no significant increase in the MCNS group. In the CRF group, B1-Ag in urine showed a significant increase in the progressive CRF group with delta s-Cr greater than 1.0 mg/dl/month as compared to the stationary CRF group with delta s-Cr less than 1.0 mg/dl/month. No correlation was observed between urinary B1-Ag and proteinuria, hematuria, s-Cr, s-BMG and u-NAG. The above findings suggested that the assay of urinary B1-Ag was useful as a new parameter in detecting the site and degree of proximal tubular damage.

Central diabetes insipidus, central hypothyroidism, renal tubular acidosis and dandy-walker syndrome: new associations.

PubMed

Alafif, M M; Aljaid, S S; Al-Agha, A E

2015-01-01

Dandy-Walker syndrome (DWS) is a rare brain malformation involving the cerebellum, and the fluid filled spaces around it, usually detected during the antenatal period or the early infancy. Clinically, it is characterized by mental retardation, developmental delay as well as cerebellar ataxia. It has been frequently associated with other conditions such as congenital heart diseases, primary hypothyroidism, and other disorders of the central nervous, gastrointestinal, genitourinary, and orthopedic systems. In this report, we describe a 3-month-old Saudi boy with the rare association of DWS with central diabetes insipidus, congenital central hypothyroidism, and type-2 renal tubular acidosis.

Central Diabetes Insipidus, Central Hypothyroidism, Renal Tubular Acidosis and Dandy-Walker Syndrome: New Associations

PubMed Central

Alafif, MM; Aljaid, SS; Al-Agha, AE

2015-01-01

Dandy-Walker syndrome (DWS) is a rare brain malformation involving the cerebellum, and the fluid filled spaces around it, usually detected during the antenatal period or the early infancy. Clinically, it is characterized by mental retardation, developmental delay as well as cerebellar ataxia. It has been frequently associated with other conditions such as congenital heart diseases, primary hypothyroidism, and other disorders of the central nervous, gastrointestinal, genitourinary, and orthopedic systems. In this report, we describe a 3-month-old Saudi boy with the rare association of DWS with central diabetes insipidus, congenital central hypothyroidism, and type-2 renal tubular acidosis. PMID:25861538

Renal tissue damage induced by focused shock waves

NASA Astrophysics Data System (ADS)

Ioritani, N.; Kuwahara, M.; Kambe, K.; Taguchi, K.; Saitoh, T.; Shirai, S.; Orikasa, S.; Takayama, K.; Lush, P. A.

1990-07-01

Biological evidence of renal arterial wall damage induced by the microjet due to shock wave-cavitation bubble interaction was demonstrated in living dog kidneys. We also intended to clarify the mechanism of renal tissue damage and the effects of different conditions of shock wave exposure (peak pressure of focused area, number of shots, exposure rate) on the renal tissue damage in comparison to stone disintegration. Disruption of arterial wall was the most remarkable histological change in the focused area of the kidneys. This lesion appeared as if the wall had been punctured by a needle. Large hematoma formation in the renal parenchym, and interstitial hemorrhage seemed to be the results of the arterial lesion. This arterial disorder also led to ischemic necrosis of the tubules surrounding the hematoma. Micro-angiographic examination of extracted kidneys also proved such arterial puncture lesions and ischemic lesions. The number of shots required for model stone disintegration was not inversely proportional to peak pressure. It decreased markedly when peak pressure was above 700 bar. Similarly thenumber of shots for hematoma formation was not inversely proportional to peak pressure, however, this decreased markedly above 500 bar. These results suggested that a hematoma could be formed under a lower peak pressure than that required for stone disintegration.

Prophylactic role of phycocyanin: a study of oxalate mediated renal cell injury.

PubMed

Farooq, Shukkur Muhammed; Asokan, Devarajan; Kalaiselvi, Periandavan; Sakthivel, Ramasamy; Varalakshmi, Palaninathan

2004-08-10

Oxalate induced renal calculi formation and the associated renal injury is thought to be caused by free radical mediated mechanisms. An in vivo model was used to investigate the effect of phycocyanin (from Spirulina platensis), a known antioxidant, against calcium oxalate urolithiasis. Male Wistar rats were divided into four groups. Hyperoxaluria was induced in two of these groups by intraperitoneal infusion of sodium oxalate (70 mg/kg) and a pretreatment of phycocyanin (100 mg/kg) as a single oral dosage was given, 1h prior to sodium oxalate infusion. An untreated control and drug control (phycocyanin alone) were also included in the study. We observed that phycocyanin significantly controlled the early biochemical changes in calcium oxalate stone formation. The antiurolithic nature of the drug was evaluated by the assessment of urinary risk factors and light microscopic observation of urinary crystals. Renal tubular damage as divulged by urinary marker enzymes (alkaline phosphatase, acid phosphatase and gamma-glutamyl transferase) and histopathological observations such as decreased tubulointerstitial, tubular dilatation and mononuclear inflammatory cells, indicated that renal damage was minimised in drug-pretreated group. Oxalate levels (P < 0.001) and lipid peroxidation (P < 0.001) in kidney tissue were significantly controlled by drug pretreatment, suggesting the ability of phycocyanin to quench the free radicals, thereby preventing the lipid peroxidation mediated tissue damage and oxalate entry. This accounts for the prevention of CaOx stones. Thus, the present analysis revealed the antioxidant and antiurolithic potential of phycocyanin thereby projecting it as a promising therapeutic agent against renal cell injury associated kidney stone formation.

Intra-tubular hydrodynamic forces influence tubulo-interstitial fibrosis in the kidney

PubMed Central

Rohatgi, Rajeev; Flores, Daniel

2010-01-01

Purpose of review Renal epithelial cells respond to mechanical stimuli with immediate transduction events (e.g., activation of ion channels), intermediate biological responses (e.g., changes in gene expression), and long term cellular adaptation (e.g., protein expression). Progressive renal disease is characterized by disturbed glomerular hydrodynamics that contributes to glomerulosclerosis, but, how intra-tubular biomechanical forces contribute to tubulo-interstital inflammation and fibrosis is poorly understood. Recent findings In vivo and in vitro models of obstructive uropathy demonstrate that tubular stretch induces robust expression of transforming growth factor β-1 (TGFβ-1), activation of tubular apoptosis, and induction of NF-κB signaling which contribute to the inflammatory and fibrotic milieu. Non-obstructive structural kidney diseases associated with nephron loss follow a course characterized by compensatory increases of single nephron glomerular filtration rate and tubular flow rate. Resulting increases in tubular fluid shear stress (FSS) reduce tissue-plasminogen activator and urokinase enzymatic activity which diminishes breakdown of extracellular matrix. In models of high dietary Na intake, which increase tubular flow, urinary TGFβ-1 concentrations and renal mitogen activated protein kinase activity are increased. Summary In conclusion, intra-tubular biomechanical forces, stretch and FSS, generate changes in intracellular signaling and gene expression that contribute to the pathobiology of obstructive, and non-obstructive kidney disease. PMID:19851105

Late renal toxicity of treatment for childhood malignancy: risk factors, long-term outcomes, and surveillance.

PubMed

Skinner, Roderick

2018-02-01

Chronic glomerular and tubular nephrotoxicity is reported in 20-50% and 20-25%, respectively, of children and adolescents treated with ifosfamide and 60-80% and 10-30%, respectively, of those given cisplatin. Up to 20% of children display evidence of chronic glomerular damage after unilateral nephrectomy for a renal tumour. Overall, childhood cancer survivors have a ninefold higher risk of developing renal failure compared with their siblings. Such chronic nephrotoxicity may have multiple causes, including chemotherapy, radiotherapy exposure to kidneys, renal surgery, supportive care drugs and tumour-related factors. These cause a wide range of chronic glomerular and tubular toxicities, often with potentially severe clinical sequelae. Many risk factors for developing nephrotoxicity, mostly patient and treatment related, have been described, but we remain unable to predict all episodes of renal damage. This implies that other factors may be involved, such as genetic polymorphisms influencing drug metabolism. Although our knowledge of the long-term outcomes of chronic nephrotoxicity is increasing, there is still much to learn, including how we can optimally predict or achieve early detection of nephrotoxicity. Greater understanding of the pathogenesis of nephrotoxicity is needed before its occurrence can be prevented.

Distal renal tubular acidosis in two children with acquired hypothyroidism.

PubMed

Guerra-Hernández, Norma E; Ordaz-López, Karen V; Vargas-Poussou, Rosa; Escobar-Pérez, Laura; García-Nieto, Víctor M

2018-04-28

Two cases of children diagnosed with renal tubular acidosis (RTA) associated with autoimmune hypothyroidism are presented. Case 1 developed an intestinal ileus at the age of five in the context of a respiratory problem. The tests performed confirmed metabolic acidosis, hyperchloraemia, hypokalaemia and nephrocalcinosis. Case 2 was diagnosed with hypothyroidism at the age of 11, and with RTA two years later. In both patients, the diagnosis of RTA was verified when decreased maximum urinary pCO 2 was found. In case 2, a proximal bicarbonate leak (type 3 RTA) was also confirmed. This was the first case to be published on the topic. The causes of RTA in patients with hypothyroidism are reviewed. The deleterious effect on the kidneys may be due to the absence of thyroid hormone and/or autoantibodies in the cases of autoimmune hypothyroidism. Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Ex vivo hyperpolarized MR spectroscopy on isolated renal tubular cells: A novel technique for cell energy phenotyping.

PubMed

Juul, Troels; Palm, Fredrik; Nielsen, Per Mose; Bertelsen, Lotte Bonde; Laustsen, Christoffer

2017-08-01

It has been demonstrated that hyperpolarized 13 C MR is a useful tool to study cultured cells. However, cells in culture can alter phenotype, which raises concerns regarding the in vivo significance of such findings. Here we investigate if metabolic phenotyping using hyperpolarized 13 C MR is suitable for cells isolated from kidney tissue, without prior cell culture. Isolation of tubular cells from freshly excised kidney tissue and treatment with either ouabain or antimycin A was investigated with hyperpolarized MR spectroscopy on a 9.4 Tesla preclinical imaging system. Isolation of tubular cells from less than 2 g of kidney tissue generally resulted in more than 10 million live tubular cells. This amount of cells was enough to yield robust signals from the conversion of 13 C-pyruvate to lactate, bicarbonate and alanine, demonstrating that metabolic flux by means of both anaerobic and aerobic pathways can be quantified using this technique. Ex vivo metabolic phenotyping using hyperpolarized 13 C MR in a preclinical system is a useful technique to study energy metabolism in freshly isolated renal tubular cells. This technique has the potential to advance our understanding of both normal cell physiology as well as pathological processes contributing to kidney disease. Magn Reson Med 78:457-461, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Renal albumin absorption in physiology and pathology.

PubMed

Birn, H; Christensen, E I

2006-02-01

Albumin is the most abundant plasmaprotein serving multiple functions as a carrier of metabolites, hormones, vitamins, and drugs, as an acid/base buffer, as antioxidant and by supporting the oncotic pressure and volume of the blood. The presence of albumin in urine is considered to be the result of the balance between glomerular filtration and tubular reabsorption. Albuminuria has been accepted as an independent risk factor and a marker for renal as well as cardiovascular disease, and during the past decade, evidence has suggested that albumin itself may cause progression of renal disease. Thus, the reduction of proteinuria and, in particular, albuminuria has become a target in itself to prevent deterioration of renal function. Studies have shown albumin and its ligands to induce expression of inflammatory and fibrogenic mediators, and it has been hypothesized that increased filtration of albumin causes excessive tubular reabsorption, resulting in inflammation and fibrosis, resulting in the loss of renal function. In addition, it is known that tubular dysfunction in itself may cause albuminuria owing to decreased reabsorption of filtered albumin, and, recently, it has been suggested that significant amounts of albumin fragments are excreted in the urine as a result of tubular degradation. Thus, although both tubular and glomerular dysfunction influences renal handling of albumin, it appears that tubular reabsorption plays a central role in mediating the effects of albumin on renal function. The present paper will review the mechanisms for tubular albumin uptake and the possible implications for the development of renal disease.

First evidence of subclinical renal tubular injury during sickle-cell crisis.

PubMed

Audard, Vincent; Moutereau, Stéphane; Vandemelebrouck, Gaetana; Habibi, Anoosha; Khellaf, Mehdi; Grimbert, Philippe; Levy, Yves; Loric, Sylvain; Renaud, Bertrand; Lang, Philippe; Godeau, Bertrand; Galactéros, Frédéric; Bartolucci, Pablo

2014-04-29

The pathophysiologic mechanisms classically involved in sickle-cell nephropathy include endothelial dysfunction and vascular occlusion. Arguments demonstrating that ischemia-reperfusion injury-related kidney damage might coincide with vaso-occlusive crisis (VOC) are lacking. In this prospective study, we sought to determine whether tubular cells and glomerular permeability might be altered during VOC. Urine neutrophil gelatinase-associated lipocalin (NGAL) levels and albumin-excretion rates (AER) of 25 patients were evaluated prospectively during 25 VOC episodes and compared to their steady state (ST) values. During VOC, white blood-cell counts (WBC) and C-reactive protein (CRP) were significantly higher than at ST but creatinine levels were comparable. Urine NGAL levels were significantly increased during VOC vs ST (P = 0.007) and remained significant when normalized to urine creatinine (P = 0.004), while AER did not change significantly. The higher urine NGAL concentration was not associated with subsequent (24-48 hour) acute kidney injury. Univariate analysis identified no significant correlations between urine NGAL levels and laboratory parameters during VOC. These results demonstrated that subclinical ischemia-reperfusion tubular injury is common during VOC and highlight the importance of hydroelectrolyte monitoring and correction during VOC.

Protective effect of epigallocatechin-3-gallate (EGCG) via Nrf2 pathway against oxalate-induced epithelial mesenchymal transition (EMT) of renal tubular cells.

PubMed

Kanlaya, Rattiyaporn; Khamchun, Supaporn; Kapincharanon, Chompunoot; Thongboonkerd, Visith

2016-07-25

This study evaluated effect of oxalate on epithelial mesenchymal transition (EMT) and potential anti-fibrotic property of epigallocatechin-3-gallate (EGCG). MDCK renal tubular cells were incubated with 0.5 mM sodium oxalate for 24-h with/without 1-h pretreatment with 25 μM EGCG. Microscopic examination, immunoblotting and immunofluorescence staining revealed that oxalate-treated cells gained mesenchymal phenotypes by fibroblast-like morphological change and increasing expression of vimentin and fibronectin, while levels of epithelial markers (E-cadherin, occludin, cytokeratin and ZO-1) were decreased. EGCG pretreatment could prevent all these changes and molecular mechanisms underlying the prevention by EGCG were most likely due to reduced production of intracellular ROS through activation of Nrf2 signaling and increased catalase anti-oxidant enzyme. Knockdown of Nrf2 by small interfering RNA (siRNA) abrogated all the effects of EGCG, confirming that the EGCG protection against oxalate-induced EMT was mediated via Nrf2. Taken together, our data indicate that oxalate turned on EMT of renal tubular cells that could be prevented by EGCG via Nrf2 pathway. These findings also shed light onto development of novel therapeutics or preventive strategies of renal fibrosis in the future.

Renal tubular acidosis type IV in hyperkalaemic patients--a fairy tale or reality?

PubMed

Haas, Christian S; Pohlenz, Inga; Lindner, Ulrich; Muck, Philip M; Arand, Jovana; Suefke, Sven; Lehnert, Hendrik

2013-05-01

Hyperkalaemia is a common feature in hospitalized patients and often attributed to drugs antagonizing the renin-angiotensin-aldosterone system (RAAS) and/or acute kidney injury (AKI), despite significantly preserved glomerular filtration rate (GFR). The objective of this study was to determine the prevalence and role of renal tubular acidosis type IV (RTA IV) in the development of significant hyperkalaemia. A single-centre retrospective study. Patients admitted to a University Hospital over 12 months. Patients with a potassium value > 6·0 mm were identified. Clinical and laboratory data were revisited, and patients with a normal anion gap metabolic acidosis were evaluated for the existence of RTA IV. A total of 57 patients having significant hyperkalaemia (>6·0 mm) were identified. Twelve patients had end-stage renal disease, while 21 patients had solely AKI or progressive chronic renal failure. RTA IV was present in 24 patients (42%), of whom 71% had pre-existing renal insufficiency because of diabetic nephropathy or tubulointerstitial nephritis. All hyperkalaemic patients with urinary/serum electrolytes suggestive of RTA IV had evidence of AKI, but creatinine levels were significantly lower (P < 0·05), while the number of drugs antagonizing the RAAS was comparable. We demonstrated that RTA IV (i) is very common in patients with hyperkalaemia; (ii) should always be suspected in hyperkalaemic patients with only moderately impaired GFR; and (iii) may result in significant hyperkalaemia in the presence of both AKI and drugs antagonizing the RAAS. © 2012 Blackwell Publishing Ltd.

Could Notch signaling pathway be a potential therapeutic option in renal diseases?

PubMed

Marquez-Exposito, Laura; Cantero-Navarro, Elena; Lavoz, Carolina; Fierro-Fernández, Marta; Poveda, Jonay; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R; Morgado-Pascual, José Luis; Orejudo, Macarena; Mezzano, Sergio; Ruiz-Ortega, Marta

2018-02-10

Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-κB pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases. Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Genotype-Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis.

PubMed

Park, Eujin; Cho, Myung Hyun; Hyun, Hye Sun; Shin, Jae Il; Lee, Joo Hoon; Park, Young Seo; Choi, Hyun Jin; Kang, Hee Gyung; Cheong, Hae Il

2018-01-01

Primary distal renal tubular acidosis (dRTA) in children is a rare genetic disorder, and three causative mutated genes have been identified: SLC4A1, ATP6V1B1, and ATP6V0A4. We analyzed the prevalence and phenotypic differences of genetic mutations in children with dRTA. A total of 17 children with dRTA were enrolled in the study. All patients underwent genetic testing for all three candidate genes. Pathogenic mutations, including six novel mutations, were detected in 15 (88.2%) patients: dominant SLC4A1 mutations in ten (58.8%) patients, recessive ATP6V0A4 mutations in three (17.6%) patients, and recessive ATP6V1B1 mutations in two (11.8%) patients. Compared to other patients, patients with SLC4A1 mutations showed an older age of onset (3.7 ± 2.6 years) and less severe metabolic acidosis at initial presentation. All patients developed nephrocalcinosis, and sensorineural hearing loss was observed in two patients with ATP6V1B1 mutations. Three (17.6%) patients had decreased renal function (chronic kidney disease stage 2), and five (29.4%) patients had persistent growth retardation at the last follow-up. Long-term prognosis showed no genotype-phenotype correlation. SLC4A1 is the most common defective gene in Korean children with dRTA. Patients with SLC4A1 mutations show later onset and milder disease severity. Long-term follow-up of hearing ability, renal function, and growth is necessary for patients with dRTA. © 2018 The Author(s). Published by S. Karger AG, Basel.

Mixed organic solvents induce renal injury in rats.

PubMed

Qin, Weisong; Xu, Zhongxiu; Lu, Yizhou; Zeng, Caihong; Zheng, Chunxia; Wang, Shengyu; Liu, Zhihong

2012-01-01

To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2:2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5-6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli.

Mixed Organic Solvents Induce Renal Injury in Rats

PubMed Central

Qin, Weisong; Xu, Zhongxiu; Lu, Yizhou; Zeng, Caihong; Zheng, Chunxia; Wang, Shengyu; Liu, Zhihong

2012-01-01

To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2∶2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5–6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli. PMID:23029287

Tubular Obstruction Leads to Progressive Proximal Tubular Injury and Atubular Glomeruli in Polycystic Kidney Disease

PubMed Central

Galarreta, Carolina I.; Grantham, Jared J.; Forbes, Michael S.; Maser, Robin L.; Wallace, Darren P.; Chevalier, Robert L.

2015-01-01

In polycystic kidney disease (PKD), renal parenchyma is destroyed by cysts, hypothesized to obstruct nephrons. A signature of unilateral ureteral obstruction, proximal tubular atrophy leads to formation of atubular glomeruli. To determine whether this process occurs in PKD, kidneys from pcy mice (moderately progressive PKD), kidneys from cpk mice (rapidly progressive PKD), and human autosomal dominant PKD were examined in early and late stages. Integrity of the glomerulotubular junction and proximal tubular mass were determined in sections stained with Lotus tetragonolobus lectin. Development of proximal tubular atrophy and atubular glomeruli was determined in serial sections of individual glomeruli. In pcy mice, most glomerulotubular junctions were normal at 20 weeks, but by 30 weeks, 56% were atrophic and 25% of glomeruli were atubular; glomerulotubular junction integrity decreased with increasing cyst area (r = 0.83, P < 0.05). In cpk mice, all glomerulotubular junctions were normal at 10 days, but by 19 days, 26% had become abnormal. In early-stage autosomal dominant PKD kidneys, 50% of glomeruli were atubular or attached to atrophic tubules; in advanced disease, 100% were abnormal. Thus, proximal tubular injury in cystic kidneys closely parallels that observed with ureteral obstruction. These findings support the hypothesis that, in renal cystic disorders, cyst-dependent obstruction of medullary and cortical tubules initiates a process culminating in widespread destruction of proximal convoluted tubules at the glomerulotubular junction. PMID:24815352

In vitro generation of renal tubular epithelial cells from fibroblasts: implications for precision and regenerative medicine in nephrology.

PubMed

Wyatt, Christina M; Dubois, Nicole

2017-02-01

Prior efforts to generate renal epithelial cells in vitro have relied on pluripotent or bone marrow-derived mesenchymal stem cells. A recent publication in Nature Cell Biology describes the generation of induced tubular epithelial cells from fibroblasts, potentially offering a novel platform for personalized drug toxicity screening and in vitro disease modeling. This report serves as a promising proof of principle study and opens future research directions, including the optimization of the reprogramming process, efficient translation to adult human fibroblasts, and the generation of highly specific functional renal cell types. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

BAG3 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1.

PubMed

Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Li, De-Tian; Du, Zhen-Xian; Wang, Hua-Qin; Wang, Yan-Qiu

2015-01-01

Previously we have demonstrated that Bcl-2-associated athanogene 3 (BAG3) is increased in renal fibrosis using a rat unilateral ureteral obstruction model. The current study investigated the role of BAG3 in renal fibrosis using transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of BAG3 in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of BAG3 induction by shorting hairpin RNA suppressed the expression of ECM proteins but had no effect on PAI-1 expression induced by TGF-β1. Forced overexpression of BAG3 selectively increased collagens. TGF-β1-induced BAG3 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. In addition, forced BAG3 overexpression blocked attenuation of collagens expression by ERK1/2 and JNK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of BAG3, which would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.

BAG3 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1

PubMed Central

Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Li, De-Tian; Du, Zhen-Xian; Wang, Hua-Qin; Wang, Yan-Qiu

2015-01-01

Previously we have demonstrated that Bcl-2-associated athanogene 3 (BAG3) is increased in renal fibrosis using a rat unilateral ureteral obstruction model. The current study investigated the role of BAG3 in renal fibrosis using transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of BAG3 in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of BAG3 induction by shorting hairpin RNA suppressed the expression of ECM proteins but had no effect on PAI-1 expression induced by TGF-β1. Forced overexpression of BAG3 selectively increased collagens. TGF-β1-induced BAG3 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. In addition, forced BAG3 overexpression blocked attenuation of collagens expression by ERK1/2 and JNK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of BAG3, which would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins. PMID:26885277

Phosphorylation of Stats at Ser727 in renal proximal tubular epithelial cells exposed to cadmium.

PubMed

Nakagawa, Junko; Nishitai, Gen; Inageda, Kiyoshi; Matsuoka, Masato

2007-11-01

The effects of cadmium exposure on serine phosphorylation of signal transducers and activators of transcription (Stats) and an upstream kinase were examined in renal proximal tubular cells. In porcine LLC-PK1 cells treated with cadmium, Stat1 and Stat3 proteins were phosphorylated at Ser727 without changing total Stat protein levels. While phosphorylated forms of the members of mitogen-activated protein kinases (MAPKs) increased in response to cadmium exposure, treatment with a p38 inhibitor, SB203580 reduced Ser727 phosphorylation of Stat1 and Stat3 markedly in LLC-PK1 cells. The expression of human matrix metalloproteinase-3 (MMP-3), a Stats-inducible gene, was found to be up-regulated in human HK-2 cells exposed to cadmium, and suppressed by preincubation with SB203580. These results suggest that cadmium might induce the phosphorylation of Stat1 and Stat3 at Ser727 via the p38 pathway at least in part, and modulate gene expression in these proximal tubular cells. Copyright © 2007 Elsevier B.V. All rights reserved.

Increased curvature of hollow fiber membranes could up-regulate differential functions of renal tubular cell layers.

PubMed

Shen, Chong; Meng, Qin; Zhang, Guoliang

2013-08-01

Tissue engineering devices as in vitro cell culture systems in scaffolds has encountered the bottleneck due to their much lower cell functions than real tissues/organs in vivo. Such situation has been improved in some extent by mimicking the cell microenvironments in vivo from either chemical or physical ways. However, microenvironmental curvature, commonly seen in real tissues/organs, has never been manipulated to regulate the cell performance in vitro. In this regard, this paper fabricated polysulfone membranes with or without polyethylene glycol modification to investigate the impact of curvature on two renal tubular cells. Regardless the varying membrane curvatures among hollow fiber membranes of different diameters and flat membrane of zero curvature, both renal cells could well attach at 4 h of seeding and form similar confluent layers at 6 days on each membrane. Nevertheless, the renal cells on hollow fibers, though showing confluent morphology as those on flat membranes, expressed higher renal functions and, moreover, the renal functions significantly increased with the membrane curvature among hollow fibers. Such upregulation on functions was unassociated with mass transport barrier of hollow fibers, because the cultures on lengthwise cut hollow fibers without mass transfer barrier showed same curvature effect on renal functions as whole hollow fibers. It could be proposed that the curvature of hollow fiber membrane approaching to the large curvature in kidney tubules increased the mechanical stress in the renal cells and thus might up-regulate the renal cell functions. In conclusion, the increase of substrate curvature could up-regulate the cell functions without altering the confluent cell morphology and this finding will facilitate the design of functional tissue engineering devices. Copyright © 2013 Wiley Periodicals, Inc.

Citrate, not phosphate, can dissolve calcium oxalate monohydrate crystals and detach these crystals from renal tubular cells.

PubMed

Chutipongtanate, Somchai; Chaiyarit, Sakdithep; Thongboonkerd, Visith

2012-08-15

Dissolution therapy of calcium oxalate monohydrate (COM) kidney stone disease has not yet been implemented due to a lack of well characterized COM dissolution agents. The present study therefore aimed to identify potential COM crystal dissolution compounds. COM crystals were treated with deionized water (negative control), 5 mM EDTA (positive control), 5 mM sodium citrate, or 5mM sodium phosphate. COM crystal dissolution activities of these compounds were evaluated by phase-contrast and video-assisted microscopic examinations, semi-quantitative analysis of crystal size, number and total mass, and spectrophotometric oxalate-dissolution assay. In addition, effects of these compounds on detachment of COM crystals, which adhered tightly onto renal tubular cell surface, were also investigated. The results showed that citrate, not phosphate, had a significant dissolution effect on COM crystals as demonstrated by significant reduction of crystal size (approximately 37% decrease), crystal number (approximately 53% decrease) and total crystal mass (approximately 72% decrease) compared to blank and negative controls. Spectrophotometric oxalate-dissolution assay successfully confirmed the COM crystal dissolution property of citrate. Moreover, citrate could detach up to 85% of the adherent COM crystals from renal tubular cell surface. These data indicate that citrate is better than phosphate for dissolution and detachment of COM crystals. Copyright © 2012 Elsevier B.V. All rights reserved.

Alpha-enolase on apical surface of renal tubular epithelial cells serves as a calcium oxalate crystal receptor

NASA Astrophysics Data System (ADS)

Fong-Ngern, Kedsarin; Thongboonkerd, Visith

2016-10-01

To search for a strategy to prevent kidney stone formation/recurrence, this study addressed the role of α-enolase on apical membrane of renal tubular cells in mediating calcium oxalate monohydrate (COM) crystal adhesion. Its presence on apical membrane and in COM crystal-bound fraction was confirmed by Western blotting and immunofluorescence staining. Pretreating MDCK cells with anti-α-enolase antibody, not isotype-controlled IgG, dramatically reduced cell-crystal adhesion. Immunofluorescence staining also confirmed the direct binding of purified α-enolase to COM crystals at {121} > {100} > {010} crystal faces. Coating COM crystals with urinary proteins diminished the crystal binding capacity to cells and purified α-enolase. Moreover, α-enolase selectively bound to COM, not other crystals. Chemico-protein interactions analysis revealed that α-enolase interacted directly with Ca2+ and Mg2+. Incubating the cells with Mg2+ prior to cell-crystal adhesion assay significantly reduced crystal binding on the cell surface, whereas preincubation with EDTA, a divalent cation chelator, completely abolished Mg2+ effect, indicating that COM and Mg2+ competitively bind to α-enolase. Taken together, we successfully confirmed the role of α-enolase as a COM crystal receptor to mediate COM crystal adhesion at apical membrane of renal tubular cells. It may also serve as a target for stone prevention by blocking cell-crystal adhesion and stone nidus formation.

The use of fibrous, supramolecular membranes and human tubular cells for renal epithelial tissue engineering: towards a suitable membrane for a bioartificial kidney.

PubMed

Dankers, Patricia Y W; Boomker, Jasper M; Huizinga-van der Vlag, Ali; Smedts, Frank M M; Harmsen, Martin C; van Luyn, Marja J A

2010-11-10

A bioartificial kidney, which is composed of a membrane cartridge with renal epithelial cells, can substitute important kidney functions in patients with renal failure. A particular challenge is the maintenance of monolayer integrity and specialized renal epithelial cell functions ex vivo. We hypothesized that this can be improved by electro-spun, supramolecular polymer membranes which show clear benefits in ease of processability. We found that after 7 d, in comparison to conventional microporous membranes, renal tubular cells cultured on top of our fibrous supramolecular membranes formed polarized monolayers, which is prerequisite for a well-functioning bioartificial kidney. In future, these supramolecular membranes allow for incorporation of peptides that may increase cell function even further.

Dragon (repulsive guidance molecule RGMb) inhibits E-cadherin expression and induces apoptosis in renal tubular epithelial cells.

PubMed

Liu, Wenjing; Li, Xiaoling; Zhao, Yueshui; Meng, Xiao-Ming; Wan, Chao; Yang, Baoxue; Lan, Hui-Yao; Lin, Herbert Y; Xia, Yin

2013-11-01

Dragon is one of the three members of the repulsive guidance molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF-β in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45-66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo.

Long-term verification of functional and structural renal damage after renal sympathetic denervation.

PubMed

Dörr, Oliver; Liebetrau, Christoph; Möllmann, Helge; Gaede, Luise; Troidl, Christian; Wiebe, Jens; Renker, Matthias; Bauer, Timm; Hamm, Christian; Nef, Holger

2016-06-01

Previous studies of renal sympathetic denervation (RSD) excluded patients with impaired renal function to avoid potential RSD-related renal damage. Measurement of the highly sensitive biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) has shown that RSD does not aggravate renal damage during the early post-procedural period. The aim of the present study was to examine the effect of RSD on blood pressure (BP) reduction and renal function after a long-term follow-up. A total of 62 consecutive patients undergoing RSD were included in this study. Serum NGAL and KIM-1 were collected prior to RSD and at 24 hr, 48 hr, and 3 months after RSD. BP measurements, antihypertensive medication use, and safety events were followed over a three-year period. Follow-up data were available over 36.9[±3.4] months in 47 of 62 (75.8%) of the initially included patients. At this time point a significant systolic BP reduction of 23 mm Hg (P > 0.001) was documented, and there were no significant changes in serum creatinine (P = 0.14), blood urea nitrogen (P = 0.33), or estimated glomerular filtration rate (eGFR) (P = 0.2) values. There were also no significant changes documented in patients with impaired renal function (eGFR < 45 mL/min) during the early post- procedural period or the long-term follow-up (P = 0.34). The results of the present study show a sustained effect of RSD on BP reduction after a three-year follow-up, and there was no evidence of renal failure. These results provide verification of the long-term safety and effectiveness of RSD, even in patients with impaired renal function. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.

PubMed

Ronzaud, Caroline; Loffing-Cueni, Dominique; Hausel, Pierrette; Debonneville, Anne; Malsure, Sumedha Ram; Fowler-Jaeger, Nicole; Boase, Natasha A; Perrier, Romain; Maillard, Marc; Yang, Baoli; Stokes, John B; Koesters, Robert; Kumar, Sharad; Hummler, Edith; Loffing, Johannes; Staub, Olivier

2013-02-01

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.

Are gadolinium-based contrast media nephrotoxic? A renal biopsy study.

PubMed

Akgun, Hulya; Gonlusen, Gulfiliz; Cartwright, Joiner; Suki, Wadi N; Truong, Luan D

2006-09-01

Gadolinium-based contrast media were originally introduced as alternatives to iodinated media for magnetic resonance imaging. Although originally thought to be nonnephrotoxic, gadolinium-based contrast media have recently been reported to be associated with acute renal failure; the mechanism and the underlying renal injury are not completely understood. We report what is, to our knowledge, the first renal biopsy in this context. A 56-year-old patient underwent 2 consecutive vascular imaging procedures in conjunction with gadolinium-based contrast medium administration. A few days later, the patient developed acute renal failure. A renal biopsy showed acute tubular cell injury including patchy tubular cell necrosis, tubular cell degeneration, and marked proliferation of tubular cells, together with mild interstitial edema and interstitial inflammation, but without significant glomerular or vascular changes. During supportive therapy, renal function was partially regained. This case emphasizes the potential nephrotoxicity of gadolinium-based contrast media and suggests that the nephrotoxicity is related to potentially reversible acute tubular cell injury.

Distal Renal Tubules Are Deficient in Aggresome Formation and Autophagy upon Aldosterone Administration

PubMed Central

Cheema, Muhammad Umar; Damkier, Helle Hasager; Nielsen, Jakob; Poulsen, Ebbe Toftgaard; Enghild, Jan J.; Fenton, Robert A.; Praetorius, Jeppe

2014-01-01

Prolonged elevations of plasma aldosterone levels are associated with renal pathogenesis. We hypothesized that renal distress could be imposed by an augmented aldosterone-induced protein turnover challenging cellular protein degradation systems of the renal tubular cells. Cellular accumulation of specific protein aggregates in rat kidneys was assessed after 7 days of aldosterone administration. Aldosterone induced intracellular accumulation of 60 s ribosomal protein L22 in protein aggregates, specifically in the distal convoluted tubules. The mineralocorticoid receptor inhibitor spironolactone abolished aldosterone-induced accumulation of these aggregates. The aldosterone-induced protein aggregates also contained proteasome 20 s subunits. The partial de-ubiquitinase ataxin-3 was not localized to the distal renal tubule protein aggregates, and the aggregates only modestly colocalized with aggresome transfer proteins dynactin p62 and histone deacetylase 6. Intracellular protein aggregation in distal renal tubules did not lead to development of classical juxta-nuclear aggresomes or to autophagosome formation. Finally, aldosterone treatment induced foci in renal cortex of epithelial vimentin expression and a loss of E-cadherin expression, as signs of cellular stress. The cellular changes occurred within high, but physiological aldosterone concentrations. We conclude that aldosterone induces protein accumulation in distal renal tubules; these aggregates are not cleared by autophagy that may lead to early renal tubular damage. PMID:25000288

Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance

PubMed Central

Jin, Jianliang; Lv, Xianhui; Chen, Lulu; Zhang, Wei; Li, Jinbo; Wang, Qian; Wang, Rong; Lu, Xiang; Miao, Dengshun

2014-01-01

To determine whether Bmi-1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3-week-old Bmi-1-/- mice were treated with the antioxidant N-acetylcysteine (NAC, 1 mg mL−1) in their drinking water, or pyrro-quinoline quinone (PQQ, 4 mg kg−1 diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle-treated Bmi1-/- and wild-type mice. Bmi-1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five-week-old vehicle-treated Bmi-1-/- mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi-1-/- mice; subsequently, this caused DNA damage, the activation of TGF-β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress-induced epithelial-to-mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi-1 knocked down HK2 cells. All phenotypic alterations caused by Bmi-1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury. PMID:24915841

Prohibitin is associated with antioxidative protection in hypoxia/reoxygenation-induced renal tubular epithelial cell injury

NASA Astrophysics Data System (ADS)

Zhou, Tian-Biao; Qin, Yuan-Han; Lei, Feng-Ying; Huang, Wei-Fang; Drummen, Gregor P. C.

2013-11-01

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. We recently demonstrated that prohibitin downregulation results in increased renal interstitial fibrosis. Here we investigated the role of oxidative stress and prohibitin expression in a hypoxia/reoxygenation injury system in renal tubular epithelial cells with lentivirus-based delivery vectors to knockdown or overexpress prohibitin. Our results show that increased prohibitin expression was negatively correlated with reactive oxygen species, malon dialdehyde, transforming-growth-factor-β1, collagen-IV, fibronectin, and apoptosis (r = -0.895, -0.764, -0.798, -0.826, -0.817, -0.735 each P < 0.01), but positively correlated with superoxide dismutase, glutathione and mitochondrial membrane potential (r = 0.807, 0.815, 0.739; each P < 0.01). We postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Expression of Renal Aquaporins in Aristolochic Acid I and Aristolactam I-Induced Nephrotoxicity.

PubMed

Li, Ji; Zhang, Liang; Jiang, ZhenZhou; He, XiuQin; Zhang, LuYong; Xu, Ming

2016-01-01

Exposure to aristolochic acid (AA) can cause AA nephropathy, which is characterized by extensive proximal tubular damage and polyuria. To test the hypothesis that polyuria might be induced by altered regulation of aquaporins (AQPs) in the kidney, different doses of AA-I or aristolactam I (AL-I) were administered intraperitoneally to Sprague-Dawley rats, and urine, blood, and kidney samples were analyzed. In addition, AQP1, AQP2, AQP4 and AQP6 expression in the kidney were determined. The results showed dose-dependent proximal tubular damage and polyuria in the AA-I- and AL-I-treated groups, and the nephrotoxicity of AL-I was higher than that of AA-I. The expression of renal AQP1, AQP2 and AQP4, but not AQP6 were significantly inhibited by AA-I and AL-I. Comparison of the inhibition potencies of AA-I and AL-I showed that AL-I was a stronger inhibitor of AQP1 expression than AA-I, while there was no difference in their effects on AQP2 and AQP4. These results suggested that AA induced renal damage and polyuria were associated with a specific decrease in the expression of renal AQP1 AQP2 and AQP4, and AL-I showed higher nephrotoxicity than AA-I, which might be attributable to the differences in their inhibition of AQP1. © 2016 S. Karger AG, Basel.

Complicated pregnancies in inherited distal renal tubular acidosis: importance of acid-base balance.

PubMed

Seeger, Harald; Salfeld, Peter; Eisel, Rüdiger; Wagner, Carsten A; Mohebbi, Nilufar

2017-06-01

Inherited distal renal tubular acidosis (dRTA) is caused by impaired urinary acid excretion resulting in hyperchloremic metabolic acidosis. Although the glomerular filtration rate (GFR) is usually preserved, and hypertension and overt proteinuria are absent, it has to be considered that patients with dRTA also suffer from chronic kidney disease (CKD) with an increased risk for adverse pregnancy-related outcomes. Typical complications of dRTA include severe hypokalemia leading to cardiac arrhythmias and paralysis, nephrolithiasis and nephrocalcinosis. Several physiologic changes occur in normal pregnancy including alterations in acid-base and electrolyte homeostasis as well as in GFR. However, data on pregnancy in women with inherited dRTA are scarce. We report the course of pregnancy in three women with hereditary dRTA. Complications observed were severe metabolic acidosis, profound hypokalemia aggravated by hyperemesis gravidarum, recurrent urinary tract infection (UTI) and ureteric obstruction leading to renal failure. However, the outcome of all five pregnancies (1 pregnancy each for mothers n. 1 and 2; 3 pregnancies for mother n. 3) was excellent due to timely interventions. Our findings highlight the importance of close nephrologic monitoring of women with inherited dRTA during pregnancy. In addition to routine assessment of creatinine and proteinuria, caregivers should especially focus on acid-base status, plasma potassium and urinary tract infections. Patients should be screened for renal obstruction in the case of typical symptoms, UTI or renal failure. Furthermore, genetic identification of the underlying mutation may (a) support early nephrologic referral during pregnancy and a better management of the affected woman, and (b) help to avoid delayed diagnosis and reduce complications in affected newborns.

Normal tubular regeneration and differentiation of the post-ischemic kidney in mice lacking vimentin.

PubMed Central

Terzi, F.; Maunoury, R.; Colucci-Guyon, E.; Babinet, C.; Federici, P.; Briand, P.; Friedlander, G.

1997-01-01

Proliferation and dedifferentiation of tubular cells are the hallmark of early regeneration after renal ischemic injury. Vimentin, a class III intermediate filament expressed only in mesenchymal cells of mature mammals, was shown to be transiently expressed in post-ischemic renal tubular epithelial cells. Vimentin re-expression was interpreted as a marker of cellular dedifferentiation, but its role in tubular regeneration after renal ischemia has also been hypothesized. This role was evaluated in mice bearing a null mutation of the vimentin gene. Expression of vimentin, proliferating cell nuclear antigen (a marker of cellular proliferation), and villin (a marker of differentiated brush-border membranes) was studied in wild-type (Vim+/+), heterozygous (Vim+/-), and homozygous (Vim-/-) mice subjected to transient ischemia of the left kidney. As expected, vimentin was detected by immunohistochemistry at the basal pole of proximal tubular cells from post-ischemic kidney in Vim+/+ and Vim+/- mice from day 2 to day 28. The expression of the reporter gene beta-galactosidase in Vim+/- and Vim-/- mice confirmed the tubular origin of vimentin. No compensatory expression of keratin could be demonstrated in Vim-/- mice. The intensity of proliferating cell nuclear antigen labeling and the pattern of villin expression were comparable in Vim-/-, Vim+/- and Vim+/+ mice at any time of the study. After 60 days, the structure of post-ischemic kidneys in Vim-/- mice was indistinguishable from that of normal non-operated kidneys in Vim+/+ mice. In conclusion, 1) the pattern of post-ischemic proximal tubular cell proliferation, differentiation, and tubular organization was not impaired in mice lacking vimentin and 2) these results suggest that the transient tubular expression of vimentin is not instrumental in tubular regeneration after renal ischemic injury. Images Figure 1 Figure 2 Figure 3 Figure 5 Figure 6 Figure 7 PMID:9094992

Albumin Overload and PINK1/Parkin Signaling-Related Mitophagy in Renal Tubular Epithelial Cells.

PubMed

Tan, Jin; Xie, Qi; Song, Shuling; Miao, Yuyang; Zhang, Qiang

2018-03-01

BACKGROUND Albumin, as a major urinary protein component, is a risk factor for chronic kidney disease progression. Mitochondrial dysfunction is one of the main causes of albumin-induced proximal tubule cells injury. Mitophagy is considered as a pivotal protective mechanism for the elimination of dysfunctional mitochondria. The objective of this research was to determine whether albumin overload-induced mitochondrial dysfunction can activate PINK1/Parkin-mediated mitophagy in renal tubular epithelial cells (TECs). MATERIAL AND METHODS Immunofluorescence assay and Western blot assay were used to detect the effects of albumin overload on autophagy marker protein LC3. Transmission electron microscopy and Western blot assay were used to investigate the role of albumin in mitochondrial injury. Western blot assay and co-localization of acidic lysosomes and mitochondria assay were employed to detect the activation of mitophagy induced by albumin. Finally, we explored the role of PINK1/Parkin signaling in albumin-induced mitophagy by inhibiting mitophagy by knockdown of PARK2 (Parkin) level. RESULTS Immunofluorescence and Western blot results showed that the expression level of LC3-II increased, and the maximum increase point was observed after 8 h of albumin treatment. Transmission electron microscopy results demonstrated that albumin overload-induced mitochondrial injury and quantity of autophagosomes increased. Additionally, expression of PINK1 and cytosolic cytochrome C increased and mitochondria cytochrome C decreased in the albumin group. The co-localization of acidic lysosomes and mitochondria demonstrated that the number of albumin overload-induced mitophagy-positive dots increased. The transient transfection of PARK2 siRNA result showed knockdown of the expression level of PARK2 can inhibit mitophagy induced by albumin. CONCLUSIONS In conclusion, our study suggests that mitochondrial dysfunction activates the PINK1/Parkin signaling and mitophagy in renal tubular

Cisplatin toxicity reduced in human cultured renal tubular cells by oxygen pretreatment.

PubMed

Kaeidi, Ayat; Rasoulian, Bahram; Hajializadeh, Zahra; Pourkhodadad, Soheila; Rezaei, Maryam

2013-01-01

Cisplatin is an effective and widely used chemotherapy agent and its side effects, particularly nephrotoxicity, limit its usage and related platinum-based drugs. Cisplatin nephrotoxicity is mainly due to extremely increase in reactive oxygen species (ROS) generation leading to kidney tubular cell death. Preconditioning with oxidative stress has been demonstrated to stimulate the cellular adaptation to subsequent severe oxidative stress. Short term oxygen pre-exposure as a mild oxidative stress may enhance some endogenous defense mechanisms, so its effect on Cisplatin induced cell death was investigated in present research. We studied the effects of hyperoxic environment pre-exposure on Cisplatin toxicity in an in-vitro model of cultured human embryonic tubular epithelial cells (AD293). Viability of AD293 cells, as evaluated by MTT-assay, was affected by Cisplatin in a time (1-4 h) dependent model. Biochemical markers of cell apoptosis were evaluated using immunoblotting. Pretreatment with nearly pure oxygen (≥90%) for 2 h significantly reduced the level of cell damage. Activated caspase 3 and Bax/Bcl-2 ratio were significantly increased in Cisplatin-treated cells. Oxygen pretreatment inhibited caspase 3 activation and decreased Bax/Bcl-2 ratio. Oxygen pre-treatment itself not showed any cytotoxicity in exposure times up to 3 h. Our data indicate that hyperoxic preconditioning reduces Cisplatin toxicity in cultured human tubular epithelial cells. The exact mechanism of protection is unclear, though enhancement of some endogenous defense mechanisms and subsequently scavenging of free oxygen radicals may play an important role.

The need for genetic study to diagnose some cases of distal renal tubular acidosis.

PubMed

Heras Benito, Manuel; Garcia-Gonzalez, Miguel A; Valdenebro Recio, María; Molina Ordás, Álvaro; Callejas Martínez, Ramiro; Rodríguez Gómez, María Astrid; Calle García, Leonardo; Sousa Silva, Lisbeth; Fernández-Reyes Luis, María José

We describe the case of a young woman who was diagnosed with advanced kidney disease, with an incidental finding of nephrocalcinosis of unknown aetiology, having been found asymptomatic throughout her life. The genetic study by panels of known genes associated with tubulointerstitial disease allowed us to discover autosomal dominant distal renal tubular acidosis associated with a de novo mutation in exon 14 of the SLC4A1 gene, which would have been impossible to diagnose clinically due to the advanced nature of the kidney disease when it was discovered. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Acoustic radiation force impulse (ARFI) elastography for detection of renal damage in children.

PubMed

Göya, Cemil; Hamidi, Cihad; Ece, Aydın; Okur, Mehmet Hanifi; Taşdemir, Bekir; Çetinçakmak, Mehmet Güli; Hattapoğlu, Salih; Teke, Memik; Şahin, Cahit

2015-01-01

Acoustic radiation force impulse (ARFI) imaging is a promising method for noninvasive evaluation of the renal parenchyma. To investigate the contribution of ARFI quantitative US elastography for the detection of renal damage in kidneys with and without vesicoureteral reflux (VUR). One hundred seventy-six kidneys of 88 children (46 male, 42 female) who had been referred for voiding cystourethrography and 20 healthy controls were prospectively investigated. Patients were assessed according to severity of renal damage on dimercaptosuccinic acid (DMSA) scintigraphy. Ninety-eight age- and gender-matched healthy children constituted the control group. Quantitative shear wave velocity (SWV) measurements were performed in the upper and lower poles and in the interpolar region of each kidney. DMSA scintigraphy was performed in 62 children (124 kidneys). Comparisons of SWV values of kidneys with and without renal damage and/or VUR were done. Significantly higher SWV values were found in non-damaged kidneys. Severely damaged kidneys had the lowest SWV values (P < 0.001). High-grade (grade V-IV) refluxing kidneys had the lowest SWV values, while non-refluxing kidneys had the highest values (P < 0.05). Significant negative correlations were found between the mean quantitative US elastography values and DMSA scarring score (r = -0.788, P < 0.001) and VUR grade (r = -0.634, P < 0.001). SWV values of the control kidneys were significantly higher than those of damaged kidneys (P < 0.05). Our findings suggest decreasing SWV of renal units with increasing grades of vesicoureteric reflux, increasing DMSA-assessed renal damage and decreasing DMSA-assessed differential function.

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

PubMed Central

Legrand, Matthieu; Mik, Egbert G; Johannes, Tanja; Payen, Didier; Ince, Can

2008-01-01

Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium–leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways’ alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed. PMID:18488066

Dragon (Repulsive Guidance Molecule RGMb) Inhibits E-cadherin Expression and Induces Apoptosis in Renal Tubular Epithelial Cells*

PubMed Central

Liu, Wenjing; Li, Xiaoling; Zhao, Yueshui; Meng, Xiao-Ming; Wan, Chao; Yang, Baoxue; Lan, Hui-Yao; Lin, Herbert Y.; Xia, Yin

2013-01-01

Dragon is one of the three members of the repulsive guidance molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF-β in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45–66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo. PMID:24052264

Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy.

PubMed

Moore, Jeremy K; Chen, Junjie; Pan, Hua; Gaut, Joseph P; Jain, Sanjay; Wickline, Samuel A

2018-06-01

To design a fluorine MRI/MR spectroscopy approach to quantify renal vascular damage after ischemia-reperfusion injury, and the therapeutic response to antithrombin nanoparticles (NPs) to protect kidney function. A total of 53 rats underwent 45 min of bilateral renal artery occlusion and were treated at reperfusion with either plain perfluorocarbon NPs or NPs functionalized with a direct thrombin inhibitor (PPACK:phenyalanine-proline-arginine-chloromethylketone). Three hours after reperfusion, kidneys underwent ex vivo fluorine MRI/MR spectroscopy at 4.7 T to quantify the extent and volume of trapped NPs, as an index of vascular damage and ischemia-reperfusion injury. Microscopic evaluation of structural damage and NP trapping in non-reperfused renal segments was performed. Serum creatinine was quantified serially over 7 days. The damaged renal cortico-medullary junction trapped a significant volume of NPs (P = 0.04), which correlated linearly (r = 0.64) with the severity of kidney injury 3 h after reperfusion. Despite global large vessel reperfusion, non-reperfusion in medullary peritubular capillaries was confirmed by MRI and microscopy, indicative of continuing hypoxia due to vascular compromise. Treatment of animals with PPACK NPs after acute kidney injury did not accelerate kidney functional recovery. Quantification of ischemia-reperfusion injury after acute kidney injury with fluorine MRI/MR spectroscopy of perfluorocarbon NPs objectively depicts the extent and severity of vascular injury and its linear relationship to renal dysfunction. The lack of kidney function improvement after early posttreatment thrombin inhibition confirms the rapid onset of ischemia-reperfusion injury as a consequence of vascular damage and non-reperfusion. The prolongation of medullary ischemia renders cortico-medullary tubular structures susceptible to continued necrosis despite restoration of large vessel flow, which suggests limitations to acute interventions after

Renoprotective Effect of Humic Acid on Renal Ischemia-Reperfusion Injury: An Experimental Study in Rats.

PubMed

Akbas, Alpaslan; Silan, Coskun; Gulpinar, Murat Tolga; Sancak, Eyup Burak; Ozkanli, Sidika Seyma; Cakir, Dilek Ulker

2015-12-01

Humic acid is an antioxidant molecule used in agriculture and livestock breeding, as well as in medicine. Our aim was to investigate the potential renoprotective effects of humic acid in a renal ischemia reperfusion model. Twenty-one rats were randomly divided into three equal groups. Intraperitoneal serum or humic acid was injected at 1, 12, and 24 h. Non-ischemic group I was evaluated as sham. The left renal artery was clamped in serum (group II) and intraperitoneal humic acid (group III) to subject to left renal ischemic reperfusion procedure. Ischemia and reperfusion time was 60 min for each. Total antioxidant status, total oxidative status, oxidative stress index, and ischemia-modified albumin levels were analyzed biochemically from the serum samples. Kidneys were evaluated histopatologically and immunohistochemically. Biochemical results showed that total oxidative status, ischemia-modified albumin, and oxidative stress index levels were significantly decreased, but total antioxidant status was increased in the humic acid group (III) compared with the ischemia group (II) On histopathological examination, renal tubular dilatation, tubular cell damage and necrosis, dilatation of Bowman's capsule, hyaline casts, and tubular cell spillage were decreased in the humic acid group (III) compared with the ischemia group (II). Immunohistochemical results showed that apoptosis was deteriorated in group III. Renal ischemia reperfusion injury was attenuated by humic acid administration. These observations indicate that humic acid may have a potential therapeutic effect on renal ischemia reperfusion injury by preventing oxidative stress.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

PubMed

Muñoz-García, Begoña; Moreno, Juan Antonio; López-Franco, Oscar; Sanz, Ana Belén; Martín-Ventura, José Luis; Blanco, Julia; Jakubowski, Aniela; Burkly, Linda C; Ortiz, Alberto; Egido, Jesús; Blanco-Colio, Luis Miguel

2009-12-01

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with

Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications

PubMed Central

2011-01-01

Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed. PMID:21251296

Berberine activates Nrf2 nuclear translocation and inhibits apoptosis induced by high glucose in renal tubular epithelial cells through a phosphatidylinositol 3-kinase/Akt-dependent mechanism.

PubMed

Zhang, Xiuli; Liang, Dan; Lian, Xu; Jiang, Yan; He, Hui; Liang, Wei; Zhao, Yue; Chi, Zhi-Hong

2016-06-01

Apoptosis of tubular epithelial cells is a major feature of diabetic kidney disease, and hyperglycemia triggers the generation of free radicals and oxidant stress in tubular cells. Berberine (BBR) is identified as a potential anti-diabetic herbal medicine due to its beneficial effects on insulin sensitivity, glucose metabolism and glycolysis. In this study, the underlying mechanisms involved in the protective effects of BBR on high glucose-induced apoptosis were explored using cultured renal tubular epithelial cells (NRK-52E cells) and human kidney proximal tubular cell line (HK-2 cells). We identified the pivotal role of phosphatidylinositol 3-kinase (PI3K)/Akt in BBR cellular defense mechanisms and revealed the novel effect of BBR on nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and heme oxygenase (HO)-1 in NRK-52E and HK-2 cells. BBR attenuated reactive oxygen species production, antioxidant defense (GSH and SOD) and oxidant-sensitive proteins (Nrf2 and HO-1), which also were blocked by LY294002 (an inhibitor of PI3K) in HG-treated NRK-52E and HK-2 cells. Furthermore, BBR improved mitochondrial function by increasing mitochondrial membrane potential. BBR-induced anti-apoptotic function was demonstrated by decreasing apoptotic proteins (cytochrome c, Bax, caspase3 and caspase9). All these findings suggest that BBR exerts the anti-apoptosis effects through activation of PI3K/Akt signal pathways and leads to activation of Nrf2 and induction of Nrf2 target genes, and consequently protecting the renal tubular epithelial cells from HG-induced apoptosis.

Intracellular Kinases Mediate Increased Translation and Secretion of Netrin-1 from Renal Tubular Epithelial Cells

PubMed Central

Jayakumar, Calpurnia; Mohamed, Riyaz; Ranganathan, Punithavathi Vilapakkam; Ramesh, Ganesan

2011-01-01

Background Netrin-1 is a laminin-related secreted protein, is highly induced after tissue injury, and may serve as a marker of injury. However, the regulation of netrin-1 production is not unknown. Current study was carried out in mouse and mouse kidney cell line (TKPTS) to determine the signaling pathways that regulate netrin-1 production in response to injury. Methods and Principal Findings Ischemia reperfusion injury of the kidney was induced in mice by clamping renal pedicle for 30 minutes. Cellular stress was induced in mouse proximal tubular epithelial cell line by treating with pervanadate, cisplatin, lipopolysaccharide, glucose or hypoxia followed by reoxygenation. Netrin-1 expression was quantified by real time RT-PCR and protein production was quantified using an ELISA kit. Cellular stress induced a large increase in netrin-1 production without increase in transcription of netrin-1 gene. Mitogen activated protein kinase, ERK mediates the drug induced netrin-1 mRNA translation increase without altering mRNA stability. Conclusion Our results suggest that netrin-1 expression is suppressed at the translational level and MAPK activation leads to rapid translation of netrin-1 mRNA in the kidney tubular epithelial cells. PMID:22046354

Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure.

PubMed

Zheng, Hong; Liu, Xuefei; Sharma, Neeru M; Li, Yulong; Pliquett, Rainer U; Patel, Kaushik P

2016-01-01

One of the key mechanisms involved in renal Na(+) retention in chronic heart failure (CHF) is activation of epithelial Na(+) channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC, resulting in renal Na(+) retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared with sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06, and plasmin 3.57 versus sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch clamp was conducted in cultured renal collecting duct M-1 cells to record Na(+) currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na(+) inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ≈2-folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid, which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na(+) retention commonly observed in CHF. © 2015 American Heart Association, Inc.

Urinary proteolytic activation of renal epithelial Na+ channels in chronic heart failure

PubMed Central

Zheng, Hong; Liu, Xuefei; Sharma, Neeru M.; Li, Yulong; Pliquett, Rainer U; Patel, Kaushik P.

2015-01-01

One of the key mechanisms involved in renal Na+ retention in chronic heart failure (CHF) is activation of epithelial Na+ channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC resulting in renal Na+ retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared to sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06 and plasmin 3.57 vs. sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch-clamp was conducted in cultured renal collecting duct M-1 cells to record Na+ currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na+ inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ~2 folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na+ retention commonly observed in CHF. PMID:26628676

Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal

PubMed Central

Du, Rui; Xia, Lin; Ning, Xiaoxuan; Liu, Limin; Sun, Wenjuan; Huang, Chen; Wang, Hanmin; Sun, Shiren

2014-01-01

Hypoxia is an important microenvironmental factor in the development of renal fibrosis; however, the underlying mechanisms are not well elucidated. Here we show that hypoxia induces Bmi1 mRNA and protein expression in human tubular epithelial cells. We further demonstrate that Bmi1 expression might be directly regulated by hypoxia-inducible factor-1a (HIF-1a) under low oxygen. Moreover, chromatin immunoprecipitation and reporter gene assay studies reveal cooperative transactivation of Bmi1 by HIF-1α and Twist. Enforced Bmi1 expression induces epithelial–mesenchymal transition (EMT), whereas silencing endogenous Bmi-1 expression reverses hypoxia-induced EMT. Up-regulation of Bmi1 leads to stabilization of Snail via modulation of PI3K/Akt signaling, whereas ablation of PI3K/Akt signaling partially rescues the phenotype of Bmi1-overexpressing cells, indicating that PI3K/Akt signaling might be a major mediator of Bmi1-induced EMT. In a rat model of obstructive nephropathy, Bmi1 expression increases in a time-dependent manner. Furthermore, we demonstrate that increased levels of Bmi1, correlated with HIF-1α and Twist, are associated with patients with chronic kidney disease. We provide in vitro and in vivo evidence that activation of HIF-1a/Twist-Bmi1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis via modulation of PI3K/Akt/Snail signaling by facilitating EMT. PMID:25009285

Urinary tract infection in small children: the evolution of renal damage over time.

PubMed

Swerkersson, Svante; Jodal, Ulf; Sixt, Rune; Stokland, Eira; Hansson, Sverker

2017-10-01

Our objective was to analyze the evolution of kidney damage over time in small children with urinary tract infection (UTI) and factors associated with progression of renal damage. From a cohort of 1003 children <2 years of age with first-time UTI, a retrospective analysis of 103 children was done. Children were selected because of renal damage at index 99m Tc-dimercaptosuccinic acid (DMSA) scintigraphy at least 3 months after UTI, and a late DMSA scan was performed after at least 2 years. Damage was classified as progression when there was a decline in differential renal function (DRF) by ≥4%, as regression when there was complete or partial resolution of uptake defects. Of 103 children, 20 showed progression, 20 regression, and 63 remained unchanged. There were no differences between groups regarding gender or age. In the progression group, 16/20 (80%) children had vesicoureteral reflux (VUR) grade III-V and 13 (65%) had recurrent UTI. In multivariable regression analysis, both VUR grade III-V and recurrent UTI were associated with progression. In the regression group, 16/20 (80%) had no VUR or grade I-II, and two (10%) had recurrent UTI. Most small children with febrile UTI do not develop renal damage and if they do the majority remain unchanged or regress over time. However, up to one-fifth of children with renal damage diagnosed after UTI are at risk of renal deterioration. These children are characterized by the presence of VUR grades III-V and recurrent febrile UTI and may benefit from follow-up.

Exosome and Microvesicle-Enriched Fractions Isolated from Mesenchymal Stem Cells by Gradient Separation Showed Different Molecular Signatures and Functions on Renal Tubular Epithelial Cells.

PubMed

Collino, Federica; Pomatto, Margherita; Bruno, Stefania; Lindoso, Rafael Soares; Tapparo, Marta; Sicheng, Wen; Quesenberry, Peter; Camussi, Giovanni

2017-04-01

Several studies have suggested that extracellular vesicles (EVs) released from mesenchymal stem cells (MSCs) may mediate MSC paracrine action on kidney regeneration. This activity has been, at least in part, ascribed to the transfer of proteins/transcription factors and different RNA species. Information on the RNA/protein content of different MSC EV subpopulations and the correlation with their biological activity is currently incomplete. The aim of this study was to evaluate the molecular composition and the functional properties on renal target cells of MSC EV sub-populations separated by gradient floatation. The results demonstrated heterogeneity in quantity and composition of MSC EVs. Two peaks of diameter were observed (90-110 and 170-190 nm). The distribution of exosomal markers and miRNAs evaluated in the twelve gradient fractions showed an enrichment in fractions with a flotation density of 1.08-1.14 g/mL. Based on this observation, we evaluated the biological activity on renal cell proliferation and apoptosis resistance of low (CF1), medium (CF2) and high (CF3) floatation density fractions. EVs derived from all fractions, were internalized by renal cells, CF1 and CF2 but not CF3 fraction stimulated significant cell proliferation. CF2 also inhibited apoptosis on renal tubular cells submitted to ischemia-reperfusion injury. Comparative miRNomic and proteomic profiles reveal a cluster of miRNAs and proteins common to all three fractions and an enrichment of selected molecules related to renal regeneration in CF2 fraction. In conclusion, the CF2 fraction enriched in exosomal markers was the most active on renal tubular cell proliferation and protection from apoptosis.

Renal alterations in feline immunodeficiency virus (FIV)-infected cats: a natural model of lentivirus-induced renal disease changes.

PubMed

Poli, Alessandro; Tozon, Natasa; Guidi, Grazia; Pistello, Mauro

2012-09-01

Human immunodeficiency virus (HIV) is associated with several renal syndromes including acute and chronic renal failures, but the underlying pathogenic mechanisms are unclear. HIV and feline immunodeficiency virus (FIV) share numerous biological and pathological features, including renal alterations. We investigated and compared the morphological changes of renal tissue of 51 experimentally and 21 naturally infected cats. Compared to the latter, the experimentally infected cats exhibited some mesangial widening and glomerulonephritis, milder proteinuria, and lower tubular and interstitial alterations. The numbers of giant protein tubular casts and tubular microcysts were also lower. In contrast, diffuse interstitial infiltrates and glomerular and interstitial amyloidosis were detected only in naturally infected cats. Similar alterations are found in HIV infected patients, thus supporting the idea of a causative role of FIV infection in renal disease, and underlining the relevance of the FIV and its natural host as an animal model for investigating lentivirus-associated nephropathy.

Segmental heterogeneity in Bcl-2, Bcl-xL and Bax expression in rat tubular epithelium after ischemia-reperfusion.

PubMed

Valdés, Francisco; Pásaro, Eduardo; Díaz, Inmaculada; Centeno, Alberto; López, Eduardo; García-Doval, Sandra; González-Roces, Severino; Alba, Alfonso; Laffon, Blanca

2008-06-01

Studies in rats with bilateral clamping of renal arteries showed transient Bcl-2, Bcl-xL and Bax expression in renal tubular epithelium following ischemia-reperfusion. However, current data on the preferential localization of specific mRNAs or proteins are limited because gene expression was not analysed at segmental level. This study analyses the mRNA expression of Bcl-2, Bcl-xL and Bax in four segments of proximal and distal tubules localized in the renal cortex and outer medulla in rat kidneys with bilateral renal clamping for 30 min and seven reperfusion times versus control animals without clamp. Proximal convoluted tubule (PCT), distal convoluted tubule (DCT), proximal straight tubule (PST) and medullary thick ascending limb (MTAL) were obtained by manual microdissection. RT-PCR was used to analyse mRNA expression at segmental level. Proximal convoluted tubule and MTAL showed early, persistent and balanced up-regulation of Bcl-2, Bcl-xL and Bax, while PST and DCT revealed only Bcl-2 and Bcl-xL, when only Bax was detected in PST. DCT expressed Bcl-xL initially, and persistent Bcl-2 later. These patterns suggest a heterogeneous apoptosis regulatory response in rat renal tubules after ischemia-reperfusion, independently of cortical or medullary location. This heterogeneity of the expression patterns of Bcl-2 genes could explain the different susceptibility to undergo apoptosis, the different threshold to ischemic damage and the different adaptive capacity to injury among these tubular segments.

Detection of occupational lead nephropathy using early renal markers.

PubMed

Kumar, B D; Krishnaswamy, K

1995-01-01

Automotive use of leaded gasoline continues to be an important source of occupational exposure to lead in India and other countries. The present study assessed the renal function and markers of early renal damage of 22 mechanics at three automobile garages. Urinary N-acetyl-3-D-glucosaminidase activity and beta-2-microglobulin levels were significantly increased in auto garage mechanics with blood leads of 30-69 micrograms/dL. A significant correlation was observed between blood lead levels and urinary N-acetyl-3-D-glucosaminidase activity but not with urine beta-2-microglobulin levels. A marginal impairment in creatinine clearance was not statistically significant. Urinary N-acetyl-3-D-glucosaminidase activity offers a sensitive monitor of blood lead and renal tubular injury.

Bridge-in-a-Backpack(TM). Task 7 : investigation of damage and repairs for concrete filled FRP tubular arches.

DOT National Transportation Integrated Search

2015-04-01

This report includes fulfillment of Task 7 of a multi-task contract to further enhance concrete filled FRP tubes, or : the Bridge in a Backpack. : Damage due to impact of the FRP shell of the concrete filled FRP tubular arch bridges has been and stil...

A Novel Therapy to Attenuate Acute Kidney Injury and Ischemic Allograft Damage after Allogenic Kidney Transplantation in Mice

PubMed Central

Gueler, Faikah; Shushakova, Nelli; Mengel, Michael; Hueper, Katja; Chen, Rongjun; Liu, Xiaokun; Park, Joon-Keun; Haller, Hermann

2015-01-01

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20–50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells. PMID:25617900

A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

PubMed

Gueler, Faikah; Shushakova, Nelli; Mengel, Michael; Hueper, Katja; Chen, Rongjun; Liu, Xiaokun; Park, Joon-Keun; Haller, Hermann; Wensvoort, Gert; Rong, Song

2015-01-01

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity.

PubMed

Homma-Takeda, Shino; Kitahara, Keisuke; Suzuki, Kyoko; Blyth, Benjamin J; Suya, Noriyoshi; Konishi, Teruaki; Terada, Yasuko; Shimada, Yoshiya

2015-12-01

Renal toxicity is a hallmark of uranium exposure, with uranium accumulating specifically in the S3 segment of the proximal tubules causing tubular damage. As the distribution, concentration and dynamics of accumulated uranium at the cellular level is not well understood, here, we report on high-resolution quantitative in situ measurements by high-energy synchrotron radiation X-ray fluorescence analysis in renal sections from a rat model of uranium-induced acute renal toxicity. One day after subcutaneous administration of uranium acetate to male Wistar rats at a dose of 0.5 mg uranium kg(-1) body weight, uranium concentration in the S3 segment of the proximal tubules was 64.9 ± 18.2 µg g(-1) , sevenfold higher than the mean renal uranium concentration (9.7 ± 2.4 µg g(-1) ). Uranium distributed into the epithelium of the S3 segment of the proximal tubules and highly concentrated uranium (50-fold above mean renal concentration) in micro-regions was found near the nuclei. These uranium levels were maintained up to 8 days post-administration, despite more rapid reductions in mean renal concentration. Two weeks after uranium administration, damaged areas were filled with regenerating tubules and morphological signs of tissue recovery, but areas of high uranium concentration (100-fold above mean renal concentration) were still found in the epithelium of regenerating tubules. These data indicate that site-specific accumulation of uranium in micro-regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney. Copyright © 2015 John Wiley & Sons, Ltd.

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

PubMed Central

Doi, Kent; Okamoto, Koji; Negishi, Kousuke; Suzuki, Yoshifumi; Nakao, Akihide; Fujita, Toshiro; Toda, Akiko; Yokomizo, Takehiko; Kita, Yoshihiro; Kihara, Yasuyuki; Ishii, Satoshi; Shimizu, Takao; Noiri, Eisei

2006-01-01

Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells. PMID:16651609

Effects of compound Shenhua tablet on renal tubular Na+-K+-ATPase in rats with acute ischemic reperfusion injury.

PubMed

Yang, Yue; Wei, Ri-bao; Zheng, Xiao-yong; Qiu, Qiang; Cui, Shao-yuan; Yin, Zhong; Shi, Suo-zhu; Chen, Xiang-mei

2014-03-01

To observe the effect of Compound Shenhua Tablet (, SHT) on the sodium-potassium- exchanging adenosinetriphosphatase (Na(+)-K(+)-ATPase) in the renal tubular epithelial cells of rats with acute ischemic reperfusion and to investigate the mechanisms underlying the effects of SHT on renal ischemic reperfusion injury (RIRI). Fifty male Wistar rats were randomly divided into the sham surgery group, model group, astragaloside group [150 mg/(kg·d)], SHT low-dose group [1.5 g/(kg·d)] and SHT high-dose group [3.0 g/(kg·d)], with 10 rats in each group. After 1 week of continuous intragastric drug administration, surgery was performed to establish the model. At either 24 or 72 h after the surgery, 5 rats in each group were sacrificed, blood biochemistry, renal pathology, immunoblot and immunohistochemical examinations were performed, and double immunofluorescence staining was observed under a laser confocal microscope. Compared with the sham surgery group, the serum creatinine (SCr) and blood urea nitrogen (BUN) levels were significantly increased, Na(+)-K(+)-ATPase protein level was decreased, and kidney injury molecule-1 (KIM-1) protein level was increased in the model group after the surgery (P<0.01 or P<0.05). Compared with the model group, the SCr, BUN, pathological scores, Na(+)-K(+)-ATPase, and the KIM-1 protein level of the three treatment groups were significantly improved at 72 h after the surgery (P<0.05 or P<0.01). And the SCr, BUN of the SHT low- and high-dose groups, and the pathological scores of the SHT high-dose group were significantly lower than those of the astragaloside group (P<0.05). The localizations of Na(+)-K(+)-ATPase and megalin of the model group were disrupted, with the distribution areas overlapping with each other and alternately arranged. The severity of the disruption was slightly milder in three treatment groups compared with that of the model group. The results of immunofluorescence staining showed that the SHT high-dose group had a

Contrast Enhanced Diagnostic Ultrasound Causes Renal Tissue Damage in a Porcine Model

PubMed Central

Miller, Douglas L.; Dou, Chunyan; Wiggins, Roger C.

2010-01-01

Objective Glomerular capillary hemorrhage (GCH) has been reported and confirmed as a consequence of contrast-enhanced diagnostic ultrasound (CEDUS) of rat kidney. This study assessed renal tissue injury in the larger porcine model. Methods The right kidneys of anesthetized pigs were imaged in 8 groups of 4 pigs. A Vingmed System Five (General Electric Co. Cincinnati OH) was used at 1.5 MHz in B-mode to intermittently scan the kidney at 4 s intervals. A Sequoia 512 (Acuson, Mountain View CA) was used in the 1.5 MHz Cadence CPS mode with intermittent agent-clearance bursts at 4 s intervals. Kidneys were scanned transabdominally, or after laparotomy through a saline standoff. The Sequoia 512 probe was placed in contact with the kidney for one group. Definity (Lantheus Medical Imaging, N. Billerica, MA) was infused at 4 μl/kg/min (diluted 33:1 in saline) for 4 min during scanning. Results Blood-filled urinary tubules were evident on the kidney surface for all groups, except for the group with the probe in contact with the kidney. GCH was found by histology in 31.7 % ± 9.8 % of glomeruli in the center of the scan plane for 1.7 MPa transabdominal scanning and 1.5 % ± 2.9 % of glomeruli in sham samples (P<0.05). In addition, hematuria was detected after scanning, and tubular obstruction occurred in some nephrons. Conclusion Renal tissue damage was induced by CEDUS in the porcine model. This result, together with previous studies in rats, support an hypothesis that GCH would occur in humans from similar CEDUS. PMID:20876892

Serum uric acid levels contribute to new renal damage in systemic lupus erythematosus patients.

PubMed

Reátegui-Sokolova, C; Ugarte-Gil, Manuel F; Gamboa-Cárdenas, Rocío V; Zevallos, Francisco; Cucho-Venegas, Jorge M; Alfaro-Lozano, José L; Medina, Mariela; Rodriguez-Bellido, Zoila; Pastor-Asurza, Cesar A; Alarcón, Graciela S; Perich-Campos, Risto A

2017-04-01

This study aims to determine whether uric acid levels contribute to new renal damage in systemic lupus erythematosus (SLE) patients. This prospective study was conducted in consecutive patients seen since 2012. Patients had a baseline visit and follow-up visits every 6 months. Patients with ≥2 visits were included; those with end-stage renal disease (regardless of dialysis or transplantation) were excluded. Renal damage was ascertained using the SLICC/ACR damage index (SDI). Univariable and multivariable Cox-regression models were performed to determine the risk of new renal damage. Uric acid was included as a continuous and dichotomous (per receiving operating characteristic curve) variable. Multivariable models were adjusted for age at diagnosis, disease duration, socioeconomic status, SLEDAI, SDI, serum creatinine, baseline use of prednisone, antimalarials, and immunosuppressive drugs. One hundred and eighty-six patients were evaluated; their mean (SD) age at diagnosis was 36.8 (13.7) years; nearly all patients were mestizo. Disease duration was 7.7 (6.8) years. Follow-up time was 2.3 (1.1) years. The SLEDAI was 5.2 (4.3) and the SDI 0.8 (1.1). Uric acid levels were 4.5 (1.3) mg/dl. During follow-up, 16 (8.6%) patients developed at least one new point in the renal domain of the SDI. In multivariable analyses, uric acid levels (continuous and dichotomous) at baseline predicted the development of new renal damage (HR 3.21 (1.39-7.42), p 0.006; HR 18.28 (2.80-119.48), p 0.002; respectively). Higher uric acid levels contribute to the development of new renal damage in SLE patients independent of other well-known risk factors for such occurrence.

Tubular Recovery after Acute Kidney Injury.

PubMed

Fattah, Hadi; Vallon, Volker

2018-05-31

A significant portion of patients who are affected by acute kidney injury (AKI) do not fully recover due to largely unclear reasons. Restoration of tubular function has been proposed to be a prerequisite for glomerular filtration rate (GFR) recovery. Proximal tubular cells dedifferentiate during the tubular injury phase, which is required for subsequent cell proliferation and replacement of lost epithelial cells. Experimental studies indicate that some cells fail to redifferentiate and continue to produce growth factors (e.g., transforming growth factor β) that can induce fibrosis. Preclinical studies provide first evidence for beneficial effects of inhibiting glucose transport in the proximal tubule in models of ischemia-reperfusion injury. Comparing renal RNA sequencing data with kidney function during recovery from varying levels of AKI may provide new cues with regard to the sequence of events and help identify key determinants of recovery from AKI. Key Messages: Tubular recovery after AKI is vital for recovery of kidney function including improvement of GFR, and likely determines which patients fully recover from AKI or progress to chronic kidney disease. There is a need to better understand the sequence of events and the processes of tubular cell proliferation and repair, including safe strategies to intervene. The temporary inhibition of selected tubular transport processes, possibly in selected nephron regions, may provide an opportunity to improve tubular cell energetics and facilitate tubular cell recovery with consequences for kidney outcome. © 2018 S. Karger AG, Basel.

Effect of Cuscuta chinensis on renal function in ischemia/reperfusion-induced acute renal failure rats.

PubMed

Shin, Sun; Lee, Yun Jung; Kim, Eun Ju; Lee, An Sook; Kang, Dae Gill; Lee, Ho Sub

2011-01-01

The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na(+), K(+), Cl(-), creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na,K-ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K-ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.

Pathogenetic role of Arg-Gly-Asp-recognizing integrins in acute renal failure. off.

PubMed Central

Goligorsky, M S; DiBona, G F

1993-01-01

Reorientation of the alpha 3 subunit of integrins from predominantly basal to the apical cell surface of cultured renal tubular epithelial cells subjected to oxidant stress has previously been demonstrated. The present study was designed to assess functional competence of ectopically expressed apical integrins. Cell-cell adhesion assay revealed enhanced cytoatractant properties of stressed cells. Stressed epithelial cells exhibited specific recognition and binding of laminin-coated latex beads. These processes were inhibited with the peptide Gly-Arg-Gly-Asp-Asn-Pro (GRGDNP) suggesting a role of RGD-recognizing integrins in augmented adhesion to stressed cells. Given that such enhanced adhesion in in vivo acute renal failure may govern tubular obstruction by desquamated epithelium, a physiological marker of patency of tubular lumen, proximal tubular pressure, was monitored in rats subjected to 60 min of renal ischemia followed by reperfusion. Proximal tubular pressure increased 2-fold after 2 hr of reperfusion in animals that had undergone 60 min of ischemia. Infusion of GRGDNP into the renal artery during reperfusion period virtually abolished an increase in proximal tubular pressure observed in ischemic acute renal failure. These in vitro and in vivo findings are consistent with the hypothesis that RGD-recognizing integrins play an important role in the pathogenesis of tubular obstruction in ischemic acute renal failure. Images Fig. 2 Fig. 3 PMID:8516318

Macrophage-stimulating protein attenuates gentamicin-induced inflammation and apoptosis in human renal proximal tubular epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Ko Eun; Kim, Eun Young; Kim, Chang Seong

2013-05-10

Highlights: •MSP/RON system is activated in rat kidney damaged by gentamicin. •MSP inhibits GM-induced cellular apoptosis and inflammation in HK-2 cells. •MSP attenuates GM-induced activation of MAPKs and NF-κB pathways in HK-2 cells. -- Abstract: The present study aimed to investigate whether macrophage-stimulating protein (MSP) treatment attenuates renal apoptosis and inflammation in gentamicin (GM)-induced tubule injury and its underlying molecular mechanisms. To examine changes in MSP and its receptor, recepteur d’origine nantais (RON) in GM-induced nephropathy, rats were injected with GM for 7 days. Human renal proximal tubular epithelial (HK-2) cells were incubated with GM for 24 h in themore » presence of different concentrations of MSP and cell viability was measured by MTT assay. Apoptosis was determined by flow cytometry of cells stained with fluorescein isothiocyanate-conjugated annexin V protein and propidium iodide. Expression of Bcl-2, Bax, caspase-3, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB), IκB-α, and mitogen-activated protein kinases (MAPKs) was analyzed by semiquantitative immunoblotting. MSP and RON expression was significantly greater in GM-treated rats, than in untreated controls. GM-treatment reduced HK-2 cell viability, an effect that was counteracted by MSP. Flow cytometry and DAPI staining revealed GM-induced apoptosis was prevented by MSP. GM reduced expression of anti-apoptotic protein Bcl-2 and induced expression of Bax and cleaved caspase 3; these effects and GM-induced expression of COX-2 and iNOS were also attenuated by MSP. GM caused MSP-reversible induction of phospho-ERK, phospho-JNK, and phospho-p38. GM induced NF-κB activation and degradation of IκB-α; the increase in nuclear NF-κB was blocked by inhibitors of ERK, JNK, p-38, or MSP pretreatment. These findings suggest that MSP attenuates GM-induced inflammation and apoptosis by inhibition of the MAPKs

Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression.

PubMed

Shen, Hong; Liu, Tongtong; Morse, Bridget L; Zhao, Yue; Zhang, Yueping; Qiu, Xi; Chen, Cliff; Lewin, Anne C; Wang, Xi-Tao; Liu, Guowen; Christopher, Lisa J; Marathe, Punit; Lai, Yurong

2015-07-01

The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism.

PubMed

Liu, Wenjing; Chen, Binbin; Wang, Yang; Meng, Chenling; Huang, Huihui; Huang, Xiao-Ru; Qin, Jinzhong; Mulay, Shrikant R; Anders, Hans-Joachim; Qiu, Andong; Yang, Baoxue; Freeman, Gordon J; Lu, Hua Jenny; Lin, Herbert Y; Zheng, Zhi-Hua; Lan, Hui-Yao; Huang, Yu; Xia, Yin

2018-02-13

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells.

Tubular inverse opal scaffolds for biomimetic vessels

NASA Astrophysics Data System (ADS)

Zhao, Ze; Wang, Jie; Lu, Jie; Yu, Yunru; Fu, Fanfan; Wang, Huan; Liu, Yuxiao; Zhao, Yuanjin; Gu, Zhongze

2016-07-01

There is a clinical need for tissue-engineered blood vessels that can be used to replace or bypass damaged arteries. The success of such grafts depends strongly on their ability to mimic native arteries; however, currently available artificial vessels are restricted by their complex processing, controversial integrity, or uncontrollable cell location and orientation. Here, we present new tubular scaffolds with specific surface microstructures for structural vessel mimicry. The tubular scaffolds are fabricated by rotationally expanding three-dimensional tubular inverse opals that are replicated from colloidal crystal templates in capillaries. Because of the ordered porous structure of the inverse opals, the expanded tubular scaffolds are imparted with circumferentially oriented elliptical pattern microstructures on their surfaces. It is demonstrated that these tailored tubular scaffolds can effectively make endothelial cells to form an integrated hollow tubular structure on their inner surface and induce smooth muscle cells to form a circumferential orientation on their outer surface. These features of our tubular scaffolds make them highly promising for the construction of biomimetic blood vessels.There is a clinical need for tissue-engineered blood vessels that can be used to replace or bypass damaged arteries. The success of such grafts depends strongly on their ability to mimic native arteries; however, currently available artificial vessels are restricted by their complex processing, controversial integrity, or uncontrollable cell location and orientation. Here, we present new tubular scaffolds with specific surface microstructures for structural vessel mimicry. The tubular scaffolds are fabricated by rotationally expanding three-dimensional tubular inverse opals that are replicated from colloidal crystal templates in capillaries. Because of the ordered porous structure of the inverse opals, the expanded tubular scaffolds are imparted with circumferentially

Toll-Like Receptor Signaling and SIGIRR in Renal Fibrosis upon Unilateral Ureteral Obstruction

PubMed Central

Allam, Ramanjaneyulu; Ryu, Mi; Clauss, Sebastian; Susanti, Heni Eka; Römmele, Christoph; Garlanda, Cecilia; Mantovani, Alberto; Anders, Hans-Joachim

2011-01-01

Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis. PMID:21544241

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

PubMed Central

Imig, John D.; Hye Khan, Md. Abdul

2018-01-01

Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function. PMID:26756638

Radon inhalation protects mice from carbon-tetrachloride-induced hepatic and renal damage.

PubMed

Kataoka, Takahiro; Nishiyama, Yuichi; Toyota, Teruaki; Yoshimoto, Masaaki; Sakoda, Akihiro; Ishimori, Yuu; Aoyama, Yutaka; Taguchi, Takehito; Yamaoka, Kiyonori

2011-12-01

We assessed whether radon inhalation provided protection from carbon tetrachloride (CCl4)-induced hepatic and renal damage in mice. Mice were subjected to intraperitoneal injection of CCl4 after inhaling approximately 18 kBq/m3 radon for 6 h. Radon inhalation significantly increased total glutathione (t-GSH) content and glutathione peroxidase (GPx) activity in the liver and kidney. Injection of CCl4 was associated with significantly higher levels of glutamic oxaloacetic transaminase (GOT) and alkaline phosphatase (ALP) activity and creatinine level in serum, and pretreatment with radon significantly decreased the GOT and ALP activity and creatinine level associated with CCl4 injection, suggesting that radon inhalation alleviates CCl4-induced hepatic and renal damage. The t-GSH contents and GPx activity in the liver and kidney of animals pretreated with radon were significantly higher than those of the CCl(4)-only group. These findings suggested that radon inhalation activated antioxidative functions and inhibited CCl4-induced hepatic and renal damage in mice.

Divergent Effects of Hypertonic Fluid Resuscitation on Renal Pathophysiological and Structural Parameters in Rat Model of Lower Body Ischemia/Reperfusion-Induced Sterile Inflammation.

PubMed

Ergin, Bulent; Zuurbier, Coert J; Kapucu, Aysegul; Ince, Can

2017-12-27

The pathogenesis of acute kidney injury (AKI) is characterized by the deterioration of tissue perfusion and oxygenation and enhanced inflammation. The purpose of this study was to investigate whether or not the hemodynamic and inflammatory effects of hypertonic saline (HS) protect the kidney by promoting renal microcirculatory oxygenation and possible deleterious effects of HS due to its high sodium content on renal functional and structural injury following ischemia/reperfusion. Mechanically ventilated and anesthetized rats were randomly divided into four groups (n = 6 per group): a sham-operated control group; a group subjected to renal ischemia for 45 min by supra-aortic occlusion followed by 2 h of reperfusion (I/R); and I/R group treated with a continuous i.v. infusion (5 mL/kg/h) of either % 0.9 NaCl (IR+NS) or %10 NaCl (I/R+HS) after releasing the clamp. Systemic and renal hemodynamic, renal cortical (CμPO2), and medullar microcirculatory pO2 (MμPO2) are measured by the oxygen-dependent quenching of the phosphorescence lifetime technique. Renal functional, inflammatory, and tissues damage parameters were also assessed. HS, but not NS, treatment restored I/R-induced reduced mean arterial pressure, CμPO2, renal oxygen deliver (DO2ren), and consumption (VO2ren). HS caused a decrease in tubular sodium reabsorption (TNa) that correlated with an elevation of fractional sodium excretion (EFNa) and urine output. HS had an anti-inflammatory effect by reducing the levels TNF-α, IL-6, and hyaluronic acid in the renal tissue samples as compared with the I/R and I/R+NS groups (P < 0.05). HS treatment was also associated with mild acidosis and an increased renal tubular damage. Despite HS resuscitation improving the systemic hemodynamics, microcirculatory oxygenation, and renal oxygen consumption as well as inflammation, it should be limited or strictly controlled for long-term use because of provoking widespread renal structural damage.

The protective effect of grape seed procyanidin extract against cadmium-induced renal oxidative damage in mice.

PubMed

Chen, Qing; Zhang, Rong; Li, Wei-min; Niu, Yu-jie; Guo, Hui-cai; Liu, Xue-hui; Hou, Yu-chun; Zhao, Li-juan

2013-11-01

As an important environmental pollutant, cadmium (Cd) can lead to serious renal damage. Grape seed procyanidins extract (GSPE), a biological active component of grape seed, has been shown to possess antioxidative effects. Here, we assessed the protective effect of GSPE on Cd-induced renal damage using animal experiment. After 30 days, the oxidative damage of kidney was evaluated through measurement of superoxide dismutase (SOD), glutathione peroxidation (GSH-Px) and malondialdehyde (MDA). Since, oxidative stress could lead to apoptosis, the renal apoptosis was measured using flow cytometer. Moreover, the expression of apoptosis-related protein Bax and Bcl-2 was analyzed by immunohistochemistry and Western blot. The results showed that Cd led to the decrease of SOD and GSH-Px activities, and the increase of MDA level, induced renal apoptosis. However, the coadministration of GSPE attenuated Cd-induced lipid peroxidation, and antagonized renal apoptosis, probably associated with the expression of Bax and Bcl-2. These data suggested that GSPE has protective effect against renal oxidative damage induced by Cd, which provide a potential natural chemopreventive agent against Cd-poisoning. Copyright © 2013 Elsevier B.V. All rights reserved.

Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat.

PubMed

Sayhan, Mustafa Burak; Kanter, Mehmet; Oguz, Serhat; Erboga, Mustafa

2012-12-01

Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions. This study was designed to investigate the effect of Urtica dioica L. (UD), in I/R induced renal injury. A total of 32 male Sprague-Dawley rats were divided into four groups: control, UD alone, I/R and I/R + UD; each group contain 8 animals. A rat model of renal I/R injury was induced by 45-min occlusion of the bilateral renal pedicles and 24-h reperfusion. In the UD group, 3 days before I/R, UD (2 ml/kg/day intraperitoneal) was administered by gastric gavage. All animals were sacrificed at the end of reperfusion and kidney tissues samples were obtained for histopathological investigation in all groups. To date, no more histopathological changes on intestinal I/R injury in rats by UD treatment have been reported. Renal I/R caused severe histopathological injury including tubular damage, atrophy dilatation, loss of brush border and hydropic epithelial cell degenerations, renal corpuscle atrophy, glomerular shrinkage, markedly focal mononuclear cell infiltrations in the kidney. UD treatment significantly attenuated the severity of intestinal I/R injury and significantly lowered tubulointerstitial damage score than the I/R group. The number of PCNA and TUNEL positive cells in the control and UD alone groups was negligible. When kidney sections were PCNA and TUNEL stained, there was a clear increase in the number of positive cells in the I/R group rats in the renal cortical tissues. However, there is a significant reduction in the activity of PCNA and TUNEL in kidney tissue of renal injury induced by renal I/R with UD therapy. Our results suggest that administration of UD attenuates renal I/R injury. These results suggest that UD treatment has a protective effect against renal damage induced by renal I/R. This protective effect is possibly due to its ability to inhibit I/R induced renal damage, apoptosis and cell proliferation.

Necrosis and apoptosis of renal tubular epithelial cells in rats exposed to 3-methyl-4-nitrophenol.

PubMed

Yue, Zhuo; She, Rui-Ping; Bao, Hui-Hui; Tian, Jijing; Yu, Pin; Zhu, Jinfeng; Chang, Lingling; Ding, Ye; Sun, Quan

2012-11-01

The 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) exists in diesel exhaust particles (DEP), and is also one of the degradation products of insecticide fenitrothion. To assess potential nephrotoxicity of PNMC, male Sprague-Dawley (SD) rats were subcutaneously dosed with PNMC at 1, 10, and 100 mg/kg/day for five consecutive days. No significant changes were detected in body weights and relative weights of kidneys by the treatment of PNMC. However, the extent of cellular necrosis was found to be severe in renal tubular epithelial cells of PNMC-treated rats. In addition, PNMC exposure significantly increased the number of terminal deoxynucleotidyle transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells compared to the control in renal tubule of PNMC-treated rats. Moreover, immunohistochemical results indicated that significant decrease in the B-cell lymphoma 2 (Bcl-2) expressions andincrease in the Bcl-2 associated × protein (Bax) expression were detected in PNMC-treated rats. The ratio of Bcl-2/Bax was also reduced significantly at PNMC-treated rats dosed at 10 or 100 mg kg(-1) . Furthermore, the significant increase of FAS (CD95/APO-1) expression was found in the groups dosed at 10 or 100 mg kg(-1) of PNMC. The expression of Caspase-3 was higher in PNMC-treated rats, compared to the control group. Our results indicated that activation of mitochondria and Caspase-3 protease may contribute to the PNMC-induced apoptosis, suggesting that PNMC could cause both necrosis and apoptosis resulting in cell death of renal epithelium cells and could induce renal toxicity. Copyright © 2011 Wiley Periodicals, Inc.

The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells.

PubMed

Koo, Tai Yeon; Lee, Jae-Ghi; Yan, Ji-Jing; Jang, Joon Young; Ju, Kyung Don; Han, Miyeun; Oh, Kook-Hwan; Ahn, Curie; Yang, Jaeseok

2017-08-01

Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69 + CD4 + , and CD44 + CD4 + T cells was attenuated, but renal Foxp3 + CD4 + Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3 + CD4 + Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights

Protective Effect of Hydroxychloroquine on Renal Damage in Patients with Lupus Nephritis: Data from LUMINA, a Multiethnic U.S. Cohort

PubMed Central

Pons-Estel, Guillermo J.; Alarcón, Graciela S.; McGwin, Gerald; Danila, Maria I.; Zhang, Jie; Bastian, Holly M.; Reveille, John D.; Vilá, Luis M.

2010-01-01

Objective To assess if hydroxychloroquine can delay renal damage development in lupus nephritis patients. Methods Lupus nephritis patients (n=256) from LUMINA (n=635), a multiethnic cohort of African Americans, Hispanics and Caucasians, age ≥16 years, disease duration ≤5 years at baseline (T0) were studied. Renal damage was defined per the SLICC Damage Index (≥1 of the following lasting at least six months: estimated/measured glomerular filtration rate <50%, 24-hour proteinuria ≥3.5 g and/or end-stage renal disease, regardless of dialysis or transplantation). Patients with renal damage before T0 were excluded (n=53). The association between hydroxychloroquine use and renal damage (as defined, or omitting proteinuria) was estimated using Cox proportional regression analyses adjusting for potentially confounders. Kaplan-Meier survival curves based on hydroxychloroquine intake or World Health Organization (WHO) Class glomerulonephritis were also derived. Results Sixty-three (31.0%) of 203 patients developed renal damage over a mean (standard deviation) disease duration of 5.2 (3.5) years. The most frequent renal damage domain item was proteinuria. Hydroxychloroquine-takers (79.3%) exhibited a lower frequency of WHO Class IV glomerulonephritis, lower disease activity and received lower glucocorticoid doses than non-takers. After adjusting for confounders, hydroxychloroquine was protective of renal damage occurrence in full (HR=0.12; 95% CI 0.02-0.97; p=0.0464) and reduced (HR=0.29; 95%CI 0.13-0.68; p=0.0043) models. Omitting proteinuria provided comparable results. The cumulative probability of renal damage occurrence was higher in hydroxychloroquine non-takers and in WHO Class IV glomerulonephritis (p<0.0001). Conclusions After adjusting for possible confounding factors the protective effect of hydroxychloroquine in retarding renal damage occurrence in SLE is still evident. PMID:19479701

Up-regulation of Serum MiR-130b-3p Level is Associated with Renal Damage in Early Lupus Nephritis

NASA Astrophysics Data System (ADS)

Wang, Wanpeng; Mou, Shan; Wang, Ling; Zhang, Minfang; Shao, Xinghua; Fang, Wei; Lu, Renhua; Qi, Chaojun; Fan, Zhuping; Cao, Qin; Wang, Qin; Fang, Yan; Ni, Zhaohui

2015-08-01

Systemic lupus erythematosus (SLE) is a common but severe autoimmune systemic inflammatory disease. Lupus nephritis (LN) is a serious complication of SLE,affecting up to 70% of SLE patients. Circulating microRNAs (miRNA) are emerging as biomarkers for pathological conditions and play significant roles in intercellular communication. In present research, serum samples from healthy control, early and late stage LN patients were used to analyze the expression profile of miRNAs by microarray. Subsequent study demonstrated that miR-130b-3p in serum of patients with early stage LN were significantly up-regulated when compared with healthy controls. In addition,we have also observed that the expression of a large amount of circulating microRNAs significantly decreased in patients with late stage LN. The further analysis found that the expression of serum miR-130b-3p was positively correlated with 24-hour proteinuria and renal chronicity index in patients with early stage LN.Transfection of renal tubular cellline(HK-2)with miR-130b-3p mimics can promote epithelial-mesenchymal transition (EMT). The opposite effects were observed when transfected with miR-130b-3p inhibitors. MiR-130b-3p negatively regulated ERBB2IP expression by directly targeting the 3‧-UTR of ERBB2IP The circulating miR-130b-3p might serve as a biomarker and play an important role in renal damage in early stage LN patients.

Calcium oxalate crystals increased enolase-1 secretion from renal tubular cells that subsequently enhanced crystal and monocyte invasion through renal interstitium.

PubMed

Chiangjong, Wararat; Thongboonkerd, Visith

2016-04-05

Calcium oxalate monohydrate (COM) crystals cause kidney stone disease by still unclear mechanisms. The present study aimed to characterize changes in secretion of proteins from basolateral compartment of renal tubular epithelial cells after exposure to COM crystals and then correlated them with the stone pathogenesis. Polarized MDCK cells were cultivated in serum-free medium with or without 100 μg/ml COM crystals for 20 h. Secreted proteins collected from the lower chamber (basolateral compartment) were then resolved in 2-D gels and visualized by Deep Purple stain (n = 5 gels/group). Spot matching and intensity analysis revealed six protein spots with significantly altered levels in COM-treated samples. These proteins were then identified by tandem mass spectrometry (Q-TOF MS/MS), including enolase-1, phosphoglycerate mutase-1, actinin, 14-3-3 protein epsilon, alpha-tubulin 2, and ubiquitin-activating enzyme E1. The increased enolase-1 level was confirmed by Western blot analysis. Functional analysis revealed that enolase-1 dramatically induced COM crystal invasion through ECM migrating chamber in a dose-dependent manner. Moreover, enolase-1 bound onto U937 monocytic cell surface markedly enhanced cell migration through the ECM migrating chamber. In summary, our data indicated that the increased secretory enolase-1 induced by COM crystals played an important role in crystal invasion and inflammatory process in renal interstitium.

Differentiation of vasoactive renal sympathetic nerve fibres.

PubMed

Dibona, G F

2000-01-01

Activation of renal sympathetic nerves produces marked changes in renal haemodynamics, tubular ion and water transport and renin secretion. This review examines information indicating that these effects are mediated by functionally specific groups of renal sympathetic nerve fibres separately innervating the renal vessels, tubules and juxtaglomerular granular cells.

[The dose-effect relationship of water fluoride levels and renal damage in children].

PubMed

Liu, Jun-Ling; Xia, Tao; Yu, Yao-Yong; Sun, Xian-Zhong; Zhu, Qilong; He, Weihong; Zhang, Ming; Wang, Aiguo

2005-05-01

To explore the dose-effect relationship of water fluoride levels and renal damage in children and observe the difference of renal function between high-loaded fluoride people and dental fluorosis people in the same water fluoride level region. 210 children were divided into seven groups in term of drinking water fluoride levels and whether they suffered from dental fluorosis. Fluoride concentrations in urine and serum and activities of urine NAG and gamma-GT were determined. The urine and serum fluoride of high-loaded fluoride people and dental fluorosis people increased compared with control, moreover fluoride contents in urine and serum increased gradually with the increase of fluoride level in drinking water. Urine NAG and gamma-GT activities significantly increased in dental fluorosis people from area of 2.58 mg/L fluoride in drinking water and in those two groups from area of 4.51 mg/L fluoride in drinking water. Moreover, there existed an obvious dose-effect relationship between the drinking water fluoride concentration and NAG and gamma-GT activity. Over 2.0 mg/L fluoride in drinking water can cause renal damage in children, and the damage degree increases with the drinking water fluoride content. Renal damage degree is not related to whether the children suffered from dental fluorosis and mainly due to water fluoride concentration.

Bcl-2 protects tubular epithelial cells from ischemia reperfusion injury by inhibiting apoptosis.

PubMed

Suzuki, Chigure; Isaka, Yoshitaka; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Takabatake, Yoshitsugu; Ito, Takahito; Takahara, Shiro; Imai, Enyu

2008-01-01

Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of graft dysfunction in kidney transplantation subjected to ischemia. The mechanism that triggers inflammation and renal injury after ischemia remains to be elucidated; however, cellular stress may induce apoptosis during the first hours and days after transplantation, which might play a crucial role in early graft dysfunction. Bcl-2 is known to inhibit apoptosis induced by the etiological factors promoting ischemia and reperfusion injury. Accordingly, we hypothesized that an augmentation of the antiapoptotic factor Bcl-2 may thus protect tubular epithelial cells by inhibiting apoptosis, thereby ameliorating the subsequent tubulointerstitial injury. We examined the effects of Bcl-2 overexpression on ischemia-reperfusion (I/R) injury using Bcl-2 transgenic mice (Bcl-2 TG) and their wild-type littermates (WT). To investigate the effects of I/R injury, the left renal artery and vein were clamped for 45 min, followed by reperfusion for 0-96 h. Bcl-2 TG exhibited decreased active caspase protein in the tubular cells, which led to a reduction in TUNEL-positive apoptotic cells. Consequently, interstitial fibrosis and phenotypic changes were ameliorated in Bcl-2 TG. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R, and subsequent interstitial injury by inhibiting tubular apoptosis.

Effect of endogenous hydrogen sulfide inhibition on structural and functional renal disturbances induced by gentamicin.

PubMed

Francescato, H D C; Chierice, J R A; Marin, E C S; Cunha, F Q; Costa, R S; Silva, C G A; Coimbra, T M

2012-03-01

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg-1·day-1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein-1·h-1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation.

Potential Use of Autologous Renal Cells from Diseased Kidneys for the Treatment of Renal Failure.

PubMed

George, Sunil K; Abolbashari, Mehran; Jackson, John D; Aboushwareb, Tamer; Atala, Anthony; Yoo, James J

2016-01-01

Chronic kidney disease (CKD) occurs when certain conditions cause the kidneys to gradually lose function. For patients with CKD, renal transplantation is the only treatment option that restores kidney function. In this study, we evaluated primary renal cells obtained from diseased kidneys to determine whether their normal phenotypic and functional characteristics are retained, and could be used for cell therapy. Primary renal cells isolated from both normal kidneys (NK) and diseased kidneys (CKD) showed similar phenotypic characteristics and growth kinetics. The expression levels of renal tubular cell markers, Aquaporin-1 and E-Cadherin, and podocyte-specific markers, WT-1 and Nephrin, were similar in both NK and CKD kidney derived cells. Using fluorescence- activated cell sorting (FACS), specific renal cell populations were identified and included proximal tubular cells (83.1% from NK and 80.3% from CKD kidneys); distal tubular cells (11.03% from NK and 10.9% from CKD kidneys); and podocytes (1.91% from NK and 1.78% from CKD kidneys). Ultra-structural analysis using scanning electron microscopy (SEM) revealed microvilli on the apical surface of cultured cells from NK and CKD samples. Moreover, transmission electron microscopy (TEM) analysis showed a similar organization of tight junctions, desmosomes, and other intracellular structures. The Na+ uptake characteristics of NK and CKD derived renal cells were also similar (24.4 mmol/L and 25 mmol/L, respectively) and no significant differences were observed in the protein uptake and transport characteristics of these two cell isolates. These results show that primary renal cells derived from diseased kidneys such as CKD have similar structural and functional characteristics to their counterparts from a normal healthy kidney (NK) when grown in vitro. This study suggests that cells derived from diseased kidney may be used as an autologous cell source for renal cell therapy, particularly in patients with CKD or end

The effect of vitamin A on renal damage following acute pyelonephritis in children: a meta-analysis of randomized controlled trials.

PubMed

Zhang, Guo-Qiang; Chen, Jin-Liang; Zhao, Yong

2016-03-01

Renal scarring after acute pyelonephritis (APN) in children is of concern and in the worst cases leads to long-term cardiovascular morbidity. There are reports that vitamin A may alleviate renal damage following APN. We conducted a meta-analysis to investigate the role of vitamin A in the alleviation of renal damage. We searched PubMed, EMBASE, the Cochrane Central Register of Controlled trials (CENTRAL, the Cochrane Library) and the Wang Fang database (Chinese) from their inception to February 3, 2015 for randomized controlled trials (RCTs) investigating vitamin A and renal damage. Primary outcome was number of patients/kidneys with renal damage, defined as persistence of photopenic lesions based on technetium-99m dimercaptosuccinic acid renal scintigraphy. We calculated pooled relative risks for renal damage in the vitamin A group. Four RCTs, involving a total of 248 patients aged 1-144 months (120 in experimental group, 128 in control group), were included in the meta-analysis. Vitamin A was inversely associated with renal damage (relative risk 0.53, 95 % confidence interval 0.43, 0.67) when compared with placebo group after an average follow-up of 5 months. Current evidence indicates that vitamin A may exert a preventive effect on renal damage in children with APN. However, this finding largely relies on a few studies of low methodological quality, i.e., high risk of selection bias, performance bias and attrition bias. Hence, high-quality and adequately powered RCTs are warranted.

Tubular inverse opal scaffolds for biomimetic vessels.

PubMed

Zhao, Ze; Wang, Jie; Lu, Jie; Yu, Yunru; Fu, Fanfan; Wang, Huan; Liu, Yuxiao; Zhao, Yuanjin; Gu, Zhongze

2016-07-14

There is a clinical need for tissue-engineered blood vessels that can be used to replace or bypass damaged arteries. The success of such grafts depends strongly on their ability to mimic native arteries; however, currently available artificial vessels are restricted by their complex processing, controversial integrity, or uncontrollable cell location and orientation. Here, we present new tubular scaffolds with specific surface microstructures for structural vessel mimicry. The tubular scaffolds are fabricated by rotationally expanding three-dimensional tubular inverse opals that are replicated from colloidal crystal templates in capillaries. Because of the ordered porous structure of the inverse opals, the expanded tubular scaffolds are imparted with circumferentially oriented elliptical pattern microstructures on their surfaces. It is demonstrated that these tailored tubular scaffolds can effectively make endothelial cells to form an integrated hollow tubular structure on their inner surface and induce smooth muscle cells to form a circumferential orientation on their outer surface. These features of our tubular scaffolds make them highly promising for the construction of biomimetic blood vessels.

Evaluation of chronic kidney disease in chronic heart failure: From biomarkers to arterial renal resistances

PubMed Central

Iacoviello, Massimo; Leone, Marta; Antoncecchi, Valeria; Ciccone, Marco Matteo

2015-01-01

Chronic kidney disease and its worsening are recurring conditions in chronic heart failure (CHF) which are independently associated with poor patient outcome. The heart and kidney share many pathophysiological mechanisms which can determine dysfunction in each organ. Cardiorenal syndrome is the condition in which these two organs negatively affect each other, therefore an accurate evaluation of renal function in the clinical setting of CHF is essential. This review aims to revise the parameters currently used to evaluate renal dysfunction in CHF with particular reference to the usefulness and the limitations of biomarkers in evaluating glomerular dysfunction and tubular damage. Moreover, it is reported the possible utility of renal arterial resistance index (a parameter associated with abnormalities in renal vascular bed) for a better assesment of kidney disfunction. PMID:25610846

Congenital renal arteriovenous fistula during the first trimester diagnosed with ultrasonography.

PubMed

Yao, Mengyun; Zhang, Qiuyan; Wang, Jing; Xiang, Feixiang; Yu, Cheng; Lv, Qing; Xie, Mingxing; Zhang, Yanrong

2017-01-01

A case of congenital renal arteriovenous fistula (AVF) complicating pregnancy with gross hematuria was managed successfully by superselective embolization with metallic coils. The patient was in the first trimester of her pregnancy at 12 weeks of gestation. The AVF was detected by color Doppler sonography and confirmed by renal arteriography. Because of its easy accessibility and absence of irradiation, ultrasound is the first choice for pregnant patients. Color Doppler ultrasound is effective in diagnosing AVF, and it is also helpful in the long-term followup after treatment. The cirsoid-type renal congenital arteriovenous fistula has a characteristic sonographic appearance with a cluster of tubular anechoic structures in the kidney, which produce continuous turbulent high-velocity flow signals and a burr-like boundary flow spectrum. When the sonographic features are present, the diagnosis of renal AVF should be made, after which renal arteriography can be performed to confirm it. Selective embolization provided a safe and effective treatment with minimal damage to the parenchyma and without compromising renal function.

Renal Blood Flow, Glomerular Filtration Rate, and Renal Oxygenation in Early Clinical Septic Shock.

PubMed

Skytte Larsson, Jenny; Krumbholz, Vitus; Enskog, Anders; Bragadottir, Gudrun; Redfors, Bengt; Ricksten, Sven-Erik

2018-06-01

Data on renal hemodynamics, function, and oxygenation in early clinical septic shock are lacking. We therefore measured renal blood flow, glomerular filtration rate, renal oxygen consumption, and oxygenation in patients with early septic shock. Prospective comparative study. General and cardiothoracic ICUs. Patients with norepinephrine-dependent early septic shock (n = 8) were studied within 24 hours after arrival in the ICU and compared with postcardiac surgery patients without acute kidney injury (comparator group, n = 58). None. Data on systemic hemodynamics and renal variables were obtained during two 30-minute periods. Renal blood flow was measured by the infusion clearance of para-aminohippuric acid, corrected for renal extraction of para-aminohippuric acid. Renal filtration fraction was measured by renal extraction of chromium-51 labeled EDTA. Renal oxygenation was estimated from renal oxygen extraction. Renal oxygen delivery (-24%; p = 0.037) and the renal blood flow-to-cardiac index ratio (-21%; p = 0.018) were lower, renal vascular resistance was higher (26%; p = 0.027), whereas renal blood flow tended to be lower (-19%; p = 0.068) in the septic group. Glomerular filtration rate (-32%; p = 0.006) and renal sodium reabsorption (-29%; p = 0.014) were both lower in the septic group. Neither renal filtration fraction nor renal oxygen consumption differed significantly between groups. Renal oxygen extraction was significantly higher in the septic group (28%; p = 0.022). In the septic group, markers of tubular injury were elevated. In early clinical septic shock, renal function was lower, which was accompanied by renal vasoconstriction, a lower renal oxygen delivery, impaired renal oxygenation, and tubular sodium reabsorption at a high oxygen cost compared with controls.

CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction.

PubMed

Buelna-Chontal, Mabel; Franco, Martha; Hernández-Esquivel, Luz; Pavón, Natalia; Rodríguez-Zavala, José S; Correa, Francisco; Jasso, Ricardo; Pichardo-Ramos, Gregorio; Santamaría, José; González-Pacheco, Héctor; Soto, Virgilia; Díaz-Ruíz, Jorge L; Chávez, Edmundo

2017-12-01

Heavy metal ions are known to produce harmful alterations on kidney function. Specifically, the accumulation of Hg 2+ in kidney tissue may induce renal failure. In this work, the protective effect of CDP-choline against the deleterious effects induced by Hg 2+ on renal function was studied. CDP-choline administered ip at a dose of 125 mg/kg body weight prevented the damage induced by Hg 2+ administration at a dose of 3 mg/kg body weight. The findings indicate that CDP-choline guards mitochondria against Hg 2+ -toxicity by preserving their ability to retain matrix content, such as accumulated Ca 2+ . This nucleotide also protected mitochondria from Hg 2+ -induced loss of the transmembrane electric gradient and from the generation of hydrogen peroxide and membrane TBARS. In addition, CDP-choline avoided the oxidative damage of mtDNA and inhibited the release of the interleukins IL-1 and IL6, recognized as markers of acute inflammatory reaction. After the administration of Hg 2+ and CDP, CDP-choline maintained nearly normal levels of renal function and creatinine clearance, as well as blood urea nitrogen (BUN) and serum creatinine. © 2017 International Federation for Cell Biology.

Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps.

PubMed

Jansen, Marcel P B; Emal, Diba; Teske, Gwendoline J D; Dessing, Mark C; Florquin, Sandrine; Roelofs, Joris J T H

2017-02-01

Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet activation exacerbates acute kidney injury. However, the mechanism of platelet activation during ischemia reperfusion injury and how platelet activation leads to tissue injury are largely unknown. Here we found that renal ischemia reperfusion injury in mice leads to increased platelet activation in immediate proximity of necrotic cell casts. Furthermore, platelet inhibition by clopidogrel decreased cell necrosis and inflammation, indicating a link between platelet activation and renal tissue damage. Necrotic tubular epithelial cells were found to release extracellular DNA, which, in turn, activated platelets, leading to platelet-granulocyte interaction and formation of neutrophil extracellular traps ex vivo. Renal ischemia reperfusion injury resulted in increased DNA-platelet and DNA-platelet-granulocyte colocalization in tissue and elevated levels of circulating extracellular DNA and platelet factor 4 in mice. After renal ischemia reperfusion injury, neutrophil extracellular traps were formed within renal tissue, which decreased when mice were treated with the platelet inhibitor clopidogrel. Thus, during renal ischemia reperfusion injury, necrotic cell-derived DNA leads to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Resveratrol prevents high glucose-induced epithelial-mesenchymal transition in renal tubular epithelial cells by inhibiting NADPH oxidase/ROS/ERK pathway.

PubMed

He, Ting; Guan, Xu; Wang, Song; Xiao, Tangli; Yang, Ke; Xu, Xinli; Wang, Junping; Zhao, Jinghong

2015-02-15

Resveratrol (RSV) is reported to have renoprotective activity against diabetic nephropathy, while the mechanisms underlying its function have not been fully elucidated. In this study, we investigate the effect and related mechanism of RSV against high glucose-induced epithelial to mesenchymal transition (EMT) in human tubular epithelial cells (HK-2). A typical EMT is induced by high glucose in HK-2 cells, accompanied by increased levels of reactive oxygen species (ROS). RSV exhibits a strong ability to inhibit high glucose-induced EMT by decreasing intracellular ROS levels via down-regulation of NADPH oxidase subunits NOX1 and NOX4. The activation of extracellular signal-regulated kinase (ERK1/2) is found to be involved in high glucose-induced EMT in HK-2 cells. RSV, like NADPH oxidase inhibitor diphenyleneiodonium, can block ERK1/2 activation induced by high glucose. Our results demonstrate that RSV is a potent agent against high glucose-induced EMT in renal tubular cells via inhibition of NADPH oxidase/ROS/ERK1/2 pathway. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effects of PEG-PLA-nano Artificial Cells Containing Hemoglobin on Kidney Function and Renal Histology in Rats

PubMed Central

Liu, Zun Chang; Chang, Thomas M.S.

2012-01-01

This study is to investigate the long-term effects of PEG-PLA nano artificial cells containing hemoglobin (NanoRBC) on renal function and renal histology after 1/3 blood volume top loading in rats. The experimental rats received one of the following infusions: NanoRBC in Ringer lactate, Ringer lactate, stroma-free hemoglobin (SFHB), polyhemoglobin (PolyHb), autologous rat whole blood (rat RBC). Blood samples were taken before infusions and on days 1, 7 and 21 after infusions for biochemistry analysis. Rats were sacrificed on day 21 after infusions and kidneys were excised for histology examination. Infusion of SFHB induced significant decrease in renal function damage evidenced by elevated serum urea, creatinine and uric acid throughout the 21 days. Kidney histology in SFHb infusion group revealed focal tubular necrosis and intraluminal cellular debris in the proximal tubules, whereas the glomeruli were not observed damaged. In all the other groups, NanoRBC, PolyHb, Ringer lactate and rat RBC, there were no abnormalities in renal biochemistry or histology. In conclusion, injection of NanoRBC did not have adverse effects on renal function nor renal histology. PMID:18979292

Quercetin protects against radiocontrast medium toxicity in human renal proximal tubular cells.

PubMed

Andreucci, Michele; Faga, Teresa; Pisani, Antonio; Serra, Raffaele; Russo, Domenico; De Sarro, Giovambattista; Michael, Ashour

2018-05-01

Radiocontrast media (RCM)-induced acute kidney injury (CI-AKI) is a major clinical problem whose pathophysiology is not well understood. Direct toxic effects on renal cells, possibly mediated by reactive oxygen species, have been postulated as contributing to CI-AKI. We investigated the effect of quercetin on human renal proximal tubular (HK-2) cells treated with the radiocontrast medium (RCM) sodium diatrizoate. Quercetin is the most widely studied flavonoid, and the most abundant flavonol present in foods. It has been suggested to have many health benefits, including angioprotective properties and anti-cancer effects. These beneficial effects have been attributed to its antioxidant properties and its ability to modulate cell signaling pathways. Incubation of HK-2 cells with 100 μM quercetin caused a decrease in cell viability and pre-treatment of HK-2 cells with 100 μM quercetin followed by incubation with 75 mgI/ml sodium diatrizoate for 2 hr caused a decrease in cell viability which was worse than in cells treated with diatrizoate alone. However, further incubation of the cells (for 22 hr) after removal of the diatrizoate and quercetin caused a recovery in cell viability in those cells previously treated with quercetin + diatrizoate and quercetin alone. Analysis of signaling molecules by Western blotting showed that in RCM-treated cells receiving initial pre-treatment with quercetin, followed by its removal, an increase in phosphorylation of Akt (Ser473), pSTAT3 (Tyr705), and FoxO3a (Thr32) as well as an induction of Pim-1 and decrease in PARP1 cleavage were observed. Quercetin may alleviate the longer-term toxic effects of RCM toxicity and its possible beneficial effects should be further investigated. © 2017 Wiley Periodicals, Inc.

Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

PubMed

Faiman, Beth M; Mangan, Patricia; Spong, Jacy; Tariman, Joseph D

2011-08-01

Kidney dysfunction is a common clinical feature of symptomatic multiple myeloma. Some degree of renal insufficiency or renal failure is present at diagnosis or will occur during the course of the disease and, if not reversed, will adversely affect overall survival and quality of life. Chronic insults to the kidneys from other illnesses, treatment, or multiple myeloma itself can further damage renal function and increase the risk for additional complications, such as anemia. Patients with multiple myeloma who have light chain (Bence Jones protein) proteinuria may experience renal failure or progress to end-stage renal disease (ESRD) and require dialysis because of light chain cast nephropathy. Kidney failure in patients with presumed multiple myeloma also may result from amyloidosis, light chain deposition disease, or acute tubular necrosis caused by nephrotoxic agents; therefore, identification of patients at risk for kidney damage is essential. The International Myeloma Foundation's Nurse Leadership Board has developed practice recommendations for screening renal function, identifying positive and negative contributing risk and environmental factors, selecting appropriate therapies and supportive care measures to decrease progression to ESRD, and enacting dialysis to reduce and manage renal complications in patients with multiple myeloma.

Fascin-1 is released from proximal tubular cells in response to calcineurin inhibitors (CNIs) and correlates with isometric vacuolization in kidney transplanted patients

PubMed Central

Jacobs-Cachá, Conxita; Torres, Irina B; López-Hellín, Joan; Cantarell, Carme; Azancot, María A; Román, Antonio; Moreso, Francesc; Serón, Daniel; Meseguer, Anna; Sarró, Eduard

2017-01-01

Immunosuppression based on calcineurin inhibitors (CNIs) has greatly improved organ transplantation, although subsequent nephrotoxicity significantly hinders treatment success. There are no currently available specific soluble biomarkers for CNI-induced nephrotoxicity and diagnosis relies on renal biopsy, which is costly, invasive and may cause complications. Accordingly, identification of non-invasive biomarkers distinguishing CNI-induced kidney tubular damage from that of other etiologies would greatly improve diagnosis and enable more precise dosage adjustment. For this purpose, HK-2 cells, widely used to model human proximal tubule, were treated with CNIs cyclosporine-A and FK506, or staurosporine as a calcineurin-independent toxic compound, and secretomes of each treatment were analyzed by proteomic means. Among the differentially secreted proteins identified, only fascin-1 was specifically released by both CNIs but not by staurosporine. To validate fascin-1 as a biomarker of CNI-induced tubular toxicity, fascin-1 levels were analyzed in serum and urine from kidney-transplanted patients under CNIs treatment presenting or not isometric vacuolization (IV), which nowadays represents the main histological hallmark of CNI-induced tubular damage. Patients with chronic kidney disease (CKD) and healthy volunteers were used as controls. Our results show that urinary fascin-1 was only significantly elevated in the subset of CNI-treated patients presenting IV. Moreover, fascin-1 anticipated the rise of sCr levels in serially collected urine samples from CNI-treated pulmonary-transplanted patients, where a decline in kidney function and serum creatinine (sCr) elevation was mainly attributed to CNIs treatment. In conclusion, our results point towards fascin-1 as a putative soluble biomarker of CNI-induced damage in the kidney tubular compartment. PMID:28979691

Fascin-1 is released from proximal tubular cells in response to calcineurin inhibitors (CNIs) and correlates with isometric vacuolization in kidney transplanted patients.

PubMed

Jacobs-Cachá, Conxita; Torres, Irina B; López-Hellín, Joan; Cantarell, Carme; Azancot, María A; Román, Antonio; Moreso, Francesc; Serón, Daniel; Meseguer, Anna; Sarró, Eduard

2017-01-01

Immunosuppression based on calcineurin inhibitors (CNIs) has greatly improved organ transplantation, although subsequent nephrotoxicity significantly hinders treatment success. There are no currently available specific soluble biomarkers for CNI-induced nephrotoxicity and diagnosis relies on renal biopsy, which is costly, invasive and may cause complications. Accordingly, identification of non-invasive biomarkers distinguishing CNI-induced kidney tubular damage from that of other etiologies would greatly improve diagnosis and enable more precise dosage adjustment. For this purpose, HK-2 cells, widely used to model human proximal tubule, were treated with CNIs cyclosporine-A and FK506, or staurosporine as a calcineurin-independent toxic compound, and secretomes of each treatment were analyzed by proteomic means. Among the differentially secreted proteins identified, only fascin-1 was specifically released by both CNIs but not by staurosporine. To validate fascin-1 as a biomarker of CNI-induced tubular toxicity, fascin-1 levels were analyzed in serum and urine from kidney-transplanted patients under CNIs treatment presenting or not isometric vacuolization (IV), which nowadays represents the main histological hallmark of CNI-induced tubular damage. Patients with chronic kidney disease (CKD) and healthy volunteers were used as controls. Our results show that urinary fascin-1 was only significantly elevated in the subset of CNI-treated patients presenting IV. Moreover, fascin-1 anticipated the rise of sCr levels in serially collected urine samples from CNI-treated pulmonary-transplanted patients, where a decline in kidney function and serum creatinine (sCr) elevation was mainly attributed to CNIs treatment. In conclusion, our results point towards fascin-1 as a putative soluble biomarker of CNI-induced damage in the kidney tubular compartment.

The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins.

PubMed

Birn, Henrik

2006-07-01

Over the past 10 years, animal studies have uncovered the molecular mechanisms for the renal tubular recovery of filtered vitamin and vitamin carrier proteins. Relatively few endocytic receptors are responsible for the proximal tubule uptake of a number of different vitamins, preventing urinary losses. In addition to vitamin conservation, tubular uptake by endocytosis is important to vitamin metabolism and homeostasis. The present review focuses on the receptors involved in renal tubular recovery of folate, vitamin B12, and their carrier proteins. The multiligand receptor megalin is important for the uptake and tubular accumulation of vitamin B12. During vitamin load, the kidney accumulates large amounts of free vitamin B12, suggesting a possible storage function. In addition, vitamin B12 is metabolized in the kidney, suggesting a role in vitamin homeostasis. The folate receptor is important for the conservation of folate, mediating endocytosis of the vitamin. Interaction between the structurally closely related, soluble folate-binding protein and megalin suggests that megalin plays an additional role in the uptake of folate bound to filtered folate-binding protein. A third endocytic receptor, the intrinsic factor-B12 receptor cubilin-amnionless complex, is essential to the renal tubular uptake of albumin, a carrier of folate. In conclusion, uptake is mediated by interaction with specific endocytic receptors also involved in the renal uptake of other vitamins and vitamin carriers. Little is known about the mechanisms regulating intracellular transport and release of vitamins, and whereas tubular uptake is a constitutive process, this may be regulated, e.g., by vitamin status.

Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Colin D.A.; Sayer, Rachel; Windass, Amy S.

2008-12-15

The aim of this study was to determine whether primary human tubular cell monolayers could provide a powerful tool with which to investigate the renal proximal tubular handling of xenobiotics. Human proximal and distal tubule/collecting duct cells were grown as monolayers on permeable filter supports. After 10 days in culture, proximal tubule cells remained differentiated and expressed a wide palette of transporters at the mRNA level including NaPi-IIa, SGLT1, SGLT2, OCT2, OCTN2, OAT1, OAT3, OAT4, MDR1, MRP2 and BCRP. At the protein level, the expression of a subset of transporters including NaPi-IIa, OAT1 and OAT3 was demonstrated using immunohistochemistry. Analysismore » of the expression of the ATP binding cassette efflux pumps MDR1, MRP2 and BCRP confirmed their apical membrane localisation. At the functional level, tubule cell monolayers retain the necessary machinery to mediate the net secretion of the prototypic substrates; PAH and creatinine. PAH secretion across the monolayer consisted of the uptake of PAH across the basolateral membrane by OAT1 and OAT3 and the apical exit of PAH by a probenecid and MK571-sensitive route consistent with actions of MRP2 or MRP4. Creatinine secretion was by OCT2-mediated uptake at the basolateral membrane and via MDR1 at the apical membrane. Functional expression of MDR1 and BCRP at the apical membrane was also demonstrated using a Hoechst 33342 dye. Similarly, measurement of calcein efflux demonstrated the functional expression of MRP2 at the apical membrane of cell monolayers. In conclusion, human tubular cell monolayers provide a powerful tool to investigate renal xenobiotic handling.« less

Effect of sulfasalazine on renal ischemia/reperfusion injury in rats.

PubMed

Cámara-Lemarroy, Carlos Rodrigo; Guzmán-de la Garza, Francisco Javier; Alarcón-Galván, Gabriela; Cordero-Pérez, Paula; Fernández-Garza, Nancy Esthela

2009-01-01

Renal ischemia/reperfusion (I/R) occurs during shock and transplant procedures, greatly affecting outcome. A definitive treatment has not been found. One of the pathophysiological bases of renal I/R injury is the activation of the transcription factor nuclear factor-kappaB (NF-KappaB). We studied the effects of sulfasalazine (SFZ), a NF-kappaB inhibitor, over renal injury in a bilateral renal I/R model in rats. Ten male Wistar rats were subjected to bilateral renal I/R for 45 min followed by 24 h of reperfusion. Half of these received 100 mg/kg SFZ orally before the induction of I/R, while the others received only saline. Five rats served as sham-operated controls. At the end of the reperfusion period, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), P-selectin, tumor necrosis factor-alpha (TNF-alpha), intracellular adhesion molecule-1 (ICAM-1), and endothelin-1 (ET-1) concentrations were determined in serum, and renal samples were taken for histological evaluation. After renal I/R, AST, LDH, BUN, TNF-alpha, ICAM-1, and ET-1 serum levels were significantly increased, and tubules were severely damaged on histological analysis, compared to sham controls. SFZ treatment reduced the AST, LDH, BUN, TNF-alpha, and ET-1 elevations, as well as the tubular damage, induced by renal I/R. Serum ICAM-1 and P-selectin were unchanged. These results show that SFZ has a protective effect over renal IR injury. The modulation of adhesion molecules probably does not play a part in these effects, but TNF-alpha and ET-1 modulation could be partly responsible for the effects we observed.

A potential adjuvant chemotherapeutics, 18β-glycyrrhetinic acid, inhibits renal tubular epithelial cells apoptosis via enhancing BMP-7 epigenetically through targeting HDAC2.

PubMed

Ma, Taotao; Huang, Cheng; Meng, Xiaoming; Li, Xiaofeng; Zhang, Yilong; Ji, Shuai; Li, Jun; Ye, Min; Liang, Hong

2016-05-05

Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by an effective adjuvant via epigenetic modification through targeting HDAC2. Molecular docking and SPR assay firstly reported that 18βGA, major metabolite of GA, could directly bind to HDAC2 and inhibit the activity of HDAC2. The effects and mechanisms of GA and 18βGA were assessed in CP-induced AKI in C57BL/6 mice, and in CP-treated HK-2 and mTEC cells lines. TUNEL and FCM results confirmed that GA and 18βGA could inhibit apoptosis of renal tubular epithelial cells induced by CP in vivo and in vitro. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by 18βGA in AKI models while siRNA BMP-7 could reduce the inhibitory effect of 18βGA on apoptosis. Results of current study indicated that 18βGA inhibited apoptosis of renal tubular epithelial cells via enhancing the level of BMP-7 epigenetically through targeting HDAC2, therefore protecting against CP-induced AKI. These available evidence, which led to an improved understanding of molecular recognition, suggested that 18βGA could serve as a potential clinical adjuvant in chemotherapy.

Combining Functional and Tubular Damage Biomarkers Improves Diagnostic Precision for Acute Kidney Injury After Cardiac Surgery

PubMed Central

Basu, Rajit K.; Wong, Hector R.; Krawczeski, Catherine D.; Wheeler, Derek S.; Manning, Peter B.; Chawla, Lakhmir S.; Devarajan, Prasad; Goldstein, Stuart L.

2015-01-01

BACKGROUND Increases in serum creatinine (ΔSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication. OBJECTIVES This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI. METHODS Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (>100% ΔSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline ≤48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to ΔSCr increases of ≤50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values. RESULTS Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than ΔSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL−/pCysC+ composite was superior to ΔSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than ΔSCr strata. CONCLUSIONS Composites of functional and tubular damage biomarkers are superior to ΔSCr for predicting discrete characteristics of AKI. PMID:25541128

Losartan prevents the imbalance between renal dopaminergic and renin angiotensin systems induced by fructose overload. L-dopa/dopamine index as new potential biomarker of renal dysfunction.

PubMed

Mikusic, Natalia Lucía Rukavina; Kouyoumdzian, Nicolás Martín; Uceda, Ana; Del Mauro, Julieta Sofía; Pandolfo, Marcela; Gironacci, Mariela Mercedes; Puyó, Ana María; Toblli, Jorge Eduardo; Fernández, Belisario Enrique; Choi, Marcelo Roberto

2018-05-01

The renin angiotensin system (RAS) and the renal dopaminergic system (RDS) act as autocrine and paracrine systems to regulate renal sodium management and inflammation and their alterations have been associated to hypertension and renal damage. Nearly 30-50% of hypertensive patients have insulin resistance (IR), with a strong correlation between hyperinsulinemia and microalbuminuria. The aim of this study was to demonstrate the existence of an imbalance between RAS and RDS associated to IR, hypertension and kidney damage induced by fructose overload (FO), as well as to establish their prevention, by pharmacological inhibition of RAS with losartan. Ninety-six male Sprague-Dawley rats were randomly divided into four groups and studied at 4, 8 and 12 weeks: control group (C4, C8 and C12; tap water to drink); fructose-overloaded group (F4, F8 and F12; 10% w/v fructose solution to drink); losartan-treated control (L) group (L4, L8 and L12; losartan 30 mg/kg/day, in drinking water); and fructose-overloaded plus losartan group (F + L4, F + L8 and F + L12, in fructose solution). FO induced metabolic and hemodynamic alterations as well as an imbalance between RAS and RDS, characterized by increased renal angiotensin II levels and AT 1 R overexpression, reduced urinary excretion of dopamine, increased excretion of L-dopa (increased L-dopa/dopamine index) and down-regulation of D 1 R and tubular dopamine transporters OCT-2, OCT-N1 and total OCTNs. This imbalance was accompanied by an overexpression of renal tubular Na + , K + -ATPase, pro-inflammatory (NF-kB, TNF-α, IL-6) and pro-fibrotic (TGF-β1 and collagen) markers and by renal damage (microalbuminuria and reduced nephrin expression). Losartan prevented the metabolic and hemodynamic alterations induced by FO from week 4. Increased urinary L-dopa/dopamine index and decreased D 1 R renal expression associated to FO were also prevented by losartan since week 4. The same pattern was observed for renal

Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction.

PubMed

Bombas, A; Stein-Oakley, A N; Baxter, K; Thomson, N M; Jablonski, P

1999-01-01

Non-allogeneic factors such as increased nephron "workload" may contribute to chronic renal allograft rejection. Reducing dietary protein from 20% to 8% was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, "tolerised" by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-beta1 mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8% lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage.

Legionella Pneumonia Complicated with Acquired Fanconi Syndrome: A Case Report.

PubMed

Koda, Ryo; Itoh, Ryo; Tsuchida, Masafumi; Ohashi, Kazumasa; Iino, Noriaki; Takada, Toshinori; Narita, Ichiei

2018-06-06

Legionella pneumonia is occasionally accompanied by renal complications; however, the cause of this remains unknown. We herein report a 70-year-old Japanese man with Legionella pneumonia who presented with hyponatremia, hypophosphatemia, and hypouricemia. The levels of urinary β2-microglobulin and N-acetyl-β-D-glucosaminidase were remarkably high, indicating severe renal tubular damage. The presence of glycosuria and aminoaciduria as well as increased fractional excretion of uric acid and decreased tubular reabsorption of phosphate indicated that the patient's condition was complicated with Fanconi syndrome. After antimicrobial therapy, the electrolyte abnormalities and renal tubular damage were completely resolved.

Increased plasma Kidney Injury Molecule-1 suggests early progressive renal decline in non-proteinuric patients with Type 1 diabetes

PubMed Central

Nowak, Natalia; Skupien, Jan; Niewczas, Monika A.; Yamanouchi, Masayuki; Major, Melissa; Croall, Stephanie; Smiles, Adam; Warram, James H.; Bonventre, Joseph V.; Krolewski, Andrzej S.

2015-01-01

Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D. PMID:26509588

Allopurinol attenuates rhabdomyolysis-associated acute kidney injury: Renal and muscular protection.

PubMed

Gois, Pedro H F; Canale, Daniele; Volpini, Rildo A; Ferreira, Daniela; Veras, Mariana M; Andrade-Oliveira, Vinicius; Câmara, Niels O S; Shimizu, Maria H M; Seguro, Antonio C

2016-12-01

Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI. Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol. Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF 2a (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis-associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade. Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication. Copyright © 2016 Elsevier Inc. All rights reserved.

A study of the role of renal nerves in the renal responses to 60° head-up tilt in the anaesthetized dog

PubMed Central

DiBona, G. F.; Johns, E. J.

1980-01-01

1. Renal responses to 10 min of 60° head-up tilt were measured in anaesthetized dogs in which renal perfusion pressure was maintained at a relatively constant value. 2. Tilting was associated with a fall in systemic blood pressure and an increase in heart rate. Renal blood flow and glomerular filtration rate remained constant while there was a significant decrease in both absolute and fractional excretion of sodium. 3. Animals which had undergone acute renal denervation were tilted. The cardiovascular responses were similar to intact animals. A fall in renal blood flow was observed but the glomerular filtration rate was maintained at a steady value during tilting. The decreased renal tubular excretion of sodium measured in intact animals was abolished. 4. Alpha-adrenergic blockade of the kidney was achieved by infusion of phentolamine into the renal artery. Tilting of these animals caused cardiovascular changes similar to those observed in control animals but renal blood flow, glomerular filtration rate and sodium handling remained unchanged. 5. Animals in which both carotid sinuses had been acutely denervated were tilted. Systemic blood pressure fell as in intact animals, but the rise in heart rate was significantly less. Renal blood flow, glomerular filtration rate and the rate of sodium excretion were unchanged. 6. A 10 min period of 60° head-up tilt in anaesthetized dogs resulted in an unchanged renal blood flow and glomerular filtration rate which was associated with a decrease in both fractional excretion of sodium and sodium excretion. The renal sympathetic nerves were shown to be responsible for these changes in tubular sodium handling which appeared to exert their action via renal tubular α-adrenergic receptors. This activation of the renal nerves appeared to be mediated by the carotid sinus baroreceptor reflex. PMID:7381761

Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA.

PubMed

Jiang, Xiaoliang; Zhang, Yanrong; Yang, Yu; Yang, Jian; Asico, Laureano D; Chen, Wei; Felder, Robin A; Armando, Ines; Jose, Pedro A; Yang, Zhiwei

2017-01-01

Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension. Copyright © 2017 the American Physiological Society.

Effect of Organophosphate Compounds on Renal Function and Transport.

DTIC Science & Technology

1983-09-15

DiBona , 15) have presented physiological data that suggest a direct role of the sympathetic nerves in renal tubular sodium reabsorption, i.e., not...tubular sodium reabsorp- tion. Amer. J. Physiol., 233 (1977) F73-81. 16. G.F. DiBona , 1.3. Zambraski, A.S. Aquilera and G.3. Kaloyanides, Neurogenic...reflex renal nerve stimulation. J. Pharuacol. Exptl. flerap.. 198 (1976a) 464-472. 29. 1.3. Zambraski, G.E. DiBona and 0.3. Kloyanides, Specificity of

Monoanionic 99mTc-tricarbonyl-aminopolycarboxylate complexes with uncharged pendant groups: Radiosynthesis and evaluation as potential renal tubular tracers.

PubMed

Lipowska, Malgorzata; Klenc, Jeffrey; Jarkas, Nashwa; Marzilli, Luigi G; Taylor, Andrew T

2017-04-01

99m Tc(CO) 3 -nitrilotriacetic acid, 99m Tc(CO) 3 (NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of 131 I-OIH but the clearance of 99m Tc(CO) 3 (NTA) and 131 I-OIH is still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic 99m Tc(CO) 3 (NTA) has a mononegative inner metal-coordination sphere and a mononegative uncoordinated carboxyl group. To evaluate alternate synthetic approaches, we assessed the importance of an uncoordinated carboxyl group, long considered essential for tubular transport, by evaluating the pharmacokinetics of three analogs with the 99m Tc(CO) 3 (NTA) metal-coordination sphere but with uncharged pendant groups. 99m Tc(CO) 3 complexes with N-(2-acetamido)iminodiacetic acid (ADA), N-(2-hydroxyethyl)iminodiacetic acid (HDA) and N-(fluoroethyl)iminodiacetic acid (FEDA) were prepared using a tricarbonyl kit and isolated by HPLC. The pharmacokinetics were evaluated in Sprague-Dawley rats, with 131 I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10min blood samples. Re(CO) 3 (FEDA), the analog of 99m Tc(CO) 3 (FEDA), was prepared and characterized. 99m Tc(CO) 3 (ADA), 99m Tc(CO) 3 (HDA) and 99m Tc(CO) 3 (FEDA) were efficiently prepared as a single species with high radiochemical purities (>99%). These new monoanionic 99m Tc(CO) 3 tracers with uncharged dangling groups all showed rapid blood clearance and high specificity for renal excretion. Activity in the urine, as a percent of 131 I-OIH at 10 and 60min, was 96% and 99% for ADA, 96% and 100% for HDA, and 100% and 99% for FEDA, respectively. Each new tracer was excreted unchanged in the urine. The Re(CO) 3 (FEDA) structure adds compelling evidence that such 99m Tc(CO) 3 (NTA) analogs have metal-coordination spheres identical to that of 99m Tc(CO) 3 (NTA). New tracers lacking the negatively

Impact of early screening for reflux in siblings on the detection of renal damage.

PubMed

Houle, Anne-Marie; Cheikhelard, Alaa; Barrieras, Diego; Rivest, Marie-Christine; Gaudreault, Valérie

2004-07-01

To assess the impact of screening siblings after detecting significant vesico-ureteric reflux (VUR) and renal scarring, as such screening might identify patients with VUR before urinary tract infections develop, but might also detect clinically insignificant VUR. We used a previously reported screening protocol to assess the clinical characteristics of patients, including the incidence of renal scarring, and their siblings, and compared the results. In all, 123 children were screened and 44 (36%) had VUR on voiding cystography. The median (range) age at screening was 9 (1-90) months. The grades of VUR detected were < III in 61% and > or = III in 39%; VUR was bilateral in 48%. In all, 37 siblings with VUR were assessed by ultrasonography; 70% were normal, including 12 (32%) children with VUR of grade > or = III. When used, renal scintigraphy was normal in 74% of siblings, vs 18% of index patients. However, when screened after 2 years old, siblings had twice the risk of already having renal damage on renal scintigraphy (P = 0.04). Early screening (< or = 2 years) appears to be more protective for avoiding renal damage than screening older patients. Thus we propose early screening in asymptomatic siblings to detect VUR before it becomes clinically significant.

Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

PubMed Central

Kouyoumdzian, Nicolás M.; Rukavina Mikusic, Natalia L.; Kravetz, María C.; Lee, Brenda M.; Carranza, Andrea; Del Mauro, Julieta S.; Pandolfo, Marcela; Gironacci, Mariela M.; Gorzalczany, Susana; Toblli, Jorge E.; Fernández, Belisario E.

2016-01-01

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects. PMID:27392042

Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats.

PubMed

Zafrani, Lara; Ergin, Bulent; Kapucu, Aysegul; Ince, Can

2016-12-20

The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Twenty-seven Wistar albino rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 7), a LPS group that received fluid resuscitation (n = 7), and a LPS group that received blood transfusion (n = 7). The mean arterial blood pressure, renal blood flow, and renal microvascular oxygenation within the kidney cortex were recorded. Acute kidney injury was assessed using the serum creatinine levels, metabolic cost, and histopathological lesions. Nitrosative stress (expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS)) within the kidney was assessed by immunohistochemistry. Hemoglobin levels, pH, serum lactate levels, and liver enzymes were measured. Fluid resuscitation and blood transfusion both significantly improved the mean arterial pressure and renal blood flow after LPS infusion. Renal microvascular oxygenation, serum creatinine levels, and tubular damage significantly improved in the LPS group that received blood transfusion compared to the group that received fluids. Moreover, the renal expression of eNOS was markedly suppressed under endotoxin challenge. Blood transfusion, but not fluid resuscitation, was able to restore the renal expression of eNOS. However, there were no significant differences in lactic acidosis or liver function between the two groups. Blood transfusion significantly improved renal function in endotoxemic rats. The specific beneficial effect of blood transfusion on the kidney could have been mediated in part by the improvements in renal microvascular oxygenation and sepsis-induced endothelial dysfunction via the restoration of eNOS expression within the kidney.

Response of human renal tubular cells to cyclosporine and sirolimus: A toxicogenomic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pallet, Nicolas; Rabant, Marion; Xu-Dubois, Yi-Chun

The molecular mechanisms involved in the potentially nephrotoxic response of tubular cells to immunosuppressive drugs remain poorly understood. Transcriptional profiles of human proximal tubular cells exposed to cyclosporine A (CsA), sirolimus (SRL) or their combination, were established using oligonucleotide microarrays. Hierarchical clustering of genes implicated in fibrotic processes showed a clear distinction between expression profiles with CsA and CsA + SRL treatments on the one hand and SRL treatment on the other. Functional analysis found that CsA and CsA + SRL treatments preferentially alter biological processes located at the cell membrane, such as ion transport or signal transduction, whereas SRLmore » modifies biological processes within the nucleus and related to transcriptional activity. Genome wide expression analysis suggested that CsA may induce an endoplasmic reticulum (ER) stress in tubular cells in vitro. Moreover we found that CsA exposure in vivo is associated with the upregulation of the ER stress marker BIP in kidney transplant biopsies. In conclusion, this toxicogenomic study highlights the molecular interaction networks that may contribute to the tubular response to CsA and SRL. These results may also offer a new working hypothesis for future research in the field of CsA nephrotoxicity. Further studies are needed to evaluate if ER stress detection in tubular cells in human biopsies can predict CsA nephrotoxicity.« less

Silencing of p53 RNA through transarterial delivery ameliorates renal tubular injury and downregulates GSK-3β expression after ischemia-reperfusion injury.

PubMed

Fujino, Takayuki; Muhib, Sharifi; Sato, Nobuyuki; Hasebe, Naoyuki

2013-12-01

p53, a pivotal protein in the apoptotic pathway, has been identified as a mediator of transcriptional responses to ischemia-reperfusion (IR) injury. The characteristics and functional significance of the p53 response in vivo are largely unknown in IR-induced kidney injury. Therapeutic opportunities of delivering small interfering RNA (siRNA) via venous injection have gained recognition; however, systemic adverse effects of siRNA therapy should be considered. To prevent IR-induced kidney injury, we tested the efficacy of transarterial administration of siRNA targeting p53 (p53 siRNA). Female C57BL/6 mice underwent unilateral renal artery ischemia for 30 min, followed by reperfusion. siRNA experiments utilized short hairpin (sh) RNA plasmid-based approaches. Transfection of shRNA was performed using cationic polymer transfection reagent. Injection of synthetic p53 shRNA into the left renal artery just after ischemia improved tubular injury, apoptosis, and the swelling of mitochondria in cells of the thick ascending limb of Henle (mTALH) at the outer medullary regions. Staining of upregulated p53 was colocalized with the inducible expression of glycogen synthase kinase-3β (GSK-3β) at mTALH after IR injury. p53 shRNA inhibited GSK-3β expression and restored β-catenin expression at mTALH. For IR-induced kidney injury, transarterial delivery of p53 siRNA is an effective pharmacological intervention. Targeting siRNA to p53 leads to an attenuation of apoptosis and mitochondrial damage through the downregulation of GSK-3β expression and upregulation of β-catenin. Local delivery of vectors such as p53 siRNA through a transaortic catheter is clinically useful in reducing the adverse effect of siRNA-related therapy.

Renal damages after extracorporeal shock wave lithotripsy evaluated by Gd-DTPA-enhanced dynamic magnetic resonance imaging.

PubMed

Umekawa, T; Kohri, K; Yamate, T; Amasaki, N; Ishikawa, Y; Takada, M; Iguchi, M; Kurita, T

1992-01-01

Renal damages after extracorporeal shock wave lithotripsy (ESWL) were evaluated by magnetic resonance imaging (MRI) including Gd-DTPA-enhanced dynamic MRI in 37 patients with renal stone by spin echo methods (T1 and T2-weighted scan) and small tip angle gradient echo method (T2-weighted scan). Sixty-eight percent of the patients had changes in the MRI findings after ESWL. The frequently observed findings were perirenal fluid collection (38%), loss of corticomedullary junction (35%), and increased signal intensity of muscle and other adjacent tissue (34%). Preoperative Gd-DTPA-enhanced dynamic MRI showed low intensity band which suggests Gd-DTPA secretion from the glomerulus into the renal tubulus. In all cases the low intensity band became unclear after ESWL because of renal contusion due to ESWL. MRI, including Gd-DTPA-enhanced dynamic MRI, is considered to be a good procedure for evaluation of renal damages due to ESWL.

Gum acacia mitigates genetic damage in adenine-induced chronic renal failure in rats.

PubMed

Ali, B H; Al Balushi, K; Al-Husseini, I; Mandel, P; Nemmar, A; Schupp, N; Ribeiro, D A

2015-12-01

Subjects with chronic renal failure (CRF) exhibit oxidative genome damage, which may predispose to carcinogenesis, and Gum acacia (GumA) ameliorates this condition in humans and animals. We evaluated here renal DNA damage and urinary excretion of four nucleic acid oxidation adducts namely 8-oxoguanine (8-oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), 8-oxoguanosine (8-oxoGuo) and 8-hydroxy-2-deoxyguanisone (8-OHdg) in rats with adenine (ADE)-induced CRF with and without GumA treatment. Twenty-four rats were divided into four equal groups and treated for 4 weeks. The first group was given normal food and water (control). The second group was given normal food and GumA (15% w/v) in drinking water. The third group was fed powder diet containing adenine (ADE) (0·75% w/w in feed). The fourth group was fed like in the third group, plus GumA in drinking water (15%, w/v). ADE feeding induced CRF (as measured by several physiological, biochemical and histological indices) and also caused a significant genetic damage and significant decreases in urinary 8-oxo Gua and 8-oxoGuo, but not in the other nucleic acids. However, concomitant GumA treatment reduced the level of genetic damage in kidney cells as detected by Comet assay and significantly reversed the effect of adenine on urinary 8-oxoGuo. Treatment with GumA is able to mitigate genetic damage in renal tissues of rats with ADE-induced CRF. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12.

PubMed

Hirsch, H H; Yakhontova, K; Lu, M; Manzetti, J

2016-03-01

BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV-specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)- and calcineurin-inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR-SP6-kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC-1 kinase inhibitor torin-1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP-12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP-12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Inhibition of WISE preserves renal allograft function.

PubMed

Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven; Ge, Xupeng; Lee, Jae; Jurisch, Anke; Zhang, Li; You, Andrew; Fitzpatrick, Vincent D; Williams, Alexia; Valente, Eliane G; Pretorius, Jim; Stevens, Jennitte L; Tipton, Barbara; Winters, Aaron G; Graham, Kevin; Harriss, Lindsey; Baker, Daniel M; Damore, Michael; Salimi-Moosavi, Hossein; Gao, Yongming; Elkhal, Abdallah; Paszty, Chris; Simonet, W Scott; Richards, William G; Tullius, Stefan G

2013-01-01

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

Effect of endogenous hydrogen sulfide inhibition on structural and functional renal disturbances induced by gentamicin

PubMed Central

Francescato, H.D.C.; Chierice, J.R.A.; Marin, E.C.S.; Cunha, F.Q.; Costa, R.S.; Silva, C.G.A.; Coimbra, T.M.

2012-01-01

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg−1·day−1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein−1·h−1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation. PMID:22331137

Clinical and biochemical findings in Mexican patients with distal renal tubular acidosis.

PubMed

Guerra-Hernández, Norma; Matos-Martínez, Mario; Ordaz-López, Karen Verónica; Camargo-Muñiz, María Dolores; Medeiros, Mara; Escobar-Pérez, Laura

2014-01-01

Renal tubular acidosis (RTA) is a rare disease characterized by a normal serum anion gap, sustained metabolic acidosis, low concentration of plasma bicarbonate, variable hyperchloremia and hypokalemia and conserved glomerular filtration rate. RTA is developed during the first year of life and produces failure to thrive and anorexia. Primary distal RTA (type 1) is a renal syndrome with a reduced ability to excrete the acid load through the collecting ducts and impairment to concentrate the urine causing polyuria and dehydration. Evaluate the current health status and describe the clinical findings and progress of Mexican patients with distal RTA. Demonstrate the distal urinary acidification defect by measuring the urinary pCO2 tension in alkaline urines. We looked for infants in tertiary care hospitals with a clinical history of normal serum anion gap, metabolic acidosis, hypokalemia, hyperchloremia, nephrocalcinosis, sensorineural hearing loss and inability for urine acidification under systemic metabolic acidosis. Biochemical analysis were performed periodically. Alkali medication was not suspended in one patient to assess urinary acidification with oral administration of sodium bicarbonate (2 mEq/Kg) and acetazolamide (500 mg/1.73 m2 body surface). Urinary pCO2 levels were determined at 60 and 90 min. Three children, one adolescent and one adult with distal RTA were found. They had an infant history of dehydration, failure to thrive, anorexia, vomiting, muscle paralysis, hypercalciuria, urinary infections, polyuria, polydipsia and polyhidramnios during pregnancy. Severe nephrocalcinosis was detected in all patients whereas sensorineural hearing loss was developed in four cases. Under the alkali medication all cases but one were normocalciuric. A patient developed kidney failure. The urinary acidification test confirmed the innability to eliminate the acid load. Early diagnosis in infancy and continuos alkali medication were of great benefit for most of the

Protocol biopsies in renal transplantation: prognostic value of structural monitoring.

PubMed

Serón, D; Moreso, F

2007-09-01

The natural history of renal allograft damage has been characterized in serial protocol biopsies. The prevalence of subclinical rejection (SCR) is maximal during the first months and it is associated with the progression of interstitial fibrosis/tubular atrophy (IF/TA) and a decreased graft survival. IF/TA rapidly progress during the first months and constitutes an independent predictor of graft survival. IF/TA associated with transplant vasculopathy, SCR, or transplant glomerulopathy implies a poorer prognosis than IF/TA without additional lesions. These observations suggest that protocol biopsies could be considered a surrogate of graft survival. Preliminary data suggest that the predictive value of protocol biopsies is not inferior to acute rejection or renal function. Additionally, protocol biopsies have been employed as a secondary efficacy variable in clinical trials. This strategy has been useful to demonstrate a decrease in the progression of IF/TA in some calcineurin-free regimens. Quantification of renal damage is associated with graft survival suggesting that quantitative parameters might improve the predictive value of protocol biopsies. Validation of protocol biopsies as a surrogate of graft survival is actively pursued, as the utility of classical surrogates of graft outcome such as acute rejection has become less useful because of its decreased prevalence with actual immunosuppression.

Interferon-γ biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells

PubMed Central

Satou, Ryousuke; Miyata, Kayoko; Gonzalez-Villalobos, Romer A.; Ingelfinger, Julie R.; Navar, L. Gabriel; Kobori, Hiroyuki

2012-01-01

Renal inflammation modulates angiotensinogen (AGT) production in renal proximal tubular cells (RPTCs) via inflammatory cytokines, including interleukin-6, tumor necrosis factor α, and interferon-γ (IFN-γ). Among these, the effects of IFN-γ on AGT regulation in RPTCs are incompletely delineated. This study aimed to elucidate mechanisms by which IFN-γ regulates AGT expression in RPTCs. RPTCs were incubated with or without IFN-γ up to 48 h. AGT expression, STAT1 and STAT3 activities, and SOCS1 expression were evaluated. RNA interference studies against STAT1, SOCS1, and STAT3 were performed to elucidate a signaling cascade. IFN-γ decreased AGT expression at 6 h (0.61±0.05, ratio to control) and 12 h (0.47±0.03). In contrast, longer exposure for 24 and 48 h increased AGT expression (1.76±0.18, EC50=3.4 ng/ml, and 1.45±0.08, respectively). IFN-γ treatment for 6 h strongly induced STAT1 phosphorylation and SOCS1 augmentation, and decreased STAT3 activity. However, STAT1 phosphorylation and SOCS1 augmentation waned at 24 h, while STAT3 activity increased. RNA interference studies revealed that activation of STAT1-SOCS1 axis decreased STAT3 activity. Thus, IFN-γ biphasically regulates AGT expression in RPTCs via STAT3 activity modulated by STAT1-SOCS1 axis, suggesting the STAT1-SOCS1 axis is important in IFN-γ-induced activation of the intrarenal renin-angiotensin system.—Satou, R., Miyata, K., Gonzalez-Villalobos, R. A., Ingelfinger, J. R., Navar, L. G., Kobori, H. Interferon-γ biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells. PMID:22302831

Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models.

PubMed

Saraf, Santosh L; Sysol, Justin R; Susma, Alexandru; Setty, Suman; Zhang, Xu; Gudehithlu, Krishnamurthy P; Arruda, Jose A L; Singh, Ashok K; Machado, Roberto F; Gordeuk, Victor R

2018-02-02

Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso-occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. Using transgenic sickle mice, we investigated the histopathologic, ultrastructural, and gene expression differences with the HbS mutation. Consistent with progressive glomerular damage, we observed progressively greater urine protein concentrations (P = 0.03), glomerular hypertrophy (P = 0.002), and glomerular cellularity (P = 0.01) in HbAA, HbAS, and HbSS mice, respectively. Ultrastructural studies demonstrated progressive podocyte foot process effacement, glomerular basement membrane thickening with reduplication, and tubular villous atrophy with the HbS mutation. Gene expression studies highlighted the differential expression of several genes involved in prostaglandin metabolism (AKR1C18), heme and iron metabolism (HbA-A2, HMOX1, SCL25A37), electrolyte balance (SLC4A1, AQP6), immunity (RSAD2, C3, UBE2O), fatty acid metabolism (FASN), hypoxia hall-mark genes (GCK, SDC3, VEGFA, ETS1, CP, BCL2), as well as genes implicated in other forms of kidney disease (PODXL, ELMO1, FRMD3, MYH9, APOA1). Pathway analysis highlighted increased gene enrichment in focal adhesion, extracellular matrix-receptor interaction, and axon guidance pathways. In summary, using transgenic sickle mice, we observed that inheritance of the HbS mutation is associated with glomerular and tubular damage and identified several candidate genes and pathways for future investigation in sickle cell trait and sickle cell anemia-related kidney disease. Copyright © 2018 Elsevier Inc. All rights reserved.

The Swedish infant high-grade reflux trial: UTI and renal damage.

PubMed

Nordenström, Josefin; Sjöström, Sofia; Sillén, Ulla; Sixt, Rune; Brandström, Per

2017-04-01

High-grade vesicoureteral reflux (VUR) in children is associated with recurrent urinary tract infection (UTI) and renal damage. Breakthrough UTI despite continuous antibiotic prophylaxis (CAP) during the first years of life is a matter of concern and evokes early intervention. We investigated whether early endoscopic treatment (ET) of VUR grade 4-5 can reduce the risk of UTI recurrence and renal scarring. This prospective, randomized, controlled, multicentre, 1-year follow-up trial comprised 77 infants, <8 months of age with VUR grade 4-5 (Table) randomized to CAP (n = 39) or ET (with prophylaxis until resolution) (n = 38). Voiding cystourethrogram, ultrasound, renal scintigraphy, and free voiding observation were performed at study entry and after 1 year. Parenchymal defects were seen in 67 (87%) children at entry, 39 (34 boys, 5 girls) of them characterized as generalized. At follow-up, renal deterioration (new scars or progress in old damaged area) and symptomatic UTIs were reported. There were 27 recurrent febrile UTIs in 6 (16%) children in the ET group and in 10 (26%) in the CAP group (p = 0.43), in eight (36%) girls and eight (15%) boys (p = 0.039). Successful VUR outcome (VUR 0-2) was seen in 22 (59%) in the ET and eight (21%) in the CAP group (p = 0.0014). Multiple recurrences were only seen in patients with persistent dilating reflux at follow-up (p = 0.019). Deterioration on scintigraphy was seen in eight children (9 kidneys) with no difference between treatment groups (p = 0.48) or sex (p = 0.17). Renal deterioration was associated with high bladder capacity (BC) and large residual volume (PVR) at 1 year (p = 0.0092 and p = 0.041). Six of the eight children with renal deterioration had a recurrent UTI (p = 0.0032). Seven of nine renal units with deterioration were seen in children with persistent VUR 3-5 at follow-up. Univariable logistic regression identified female sex and high PVR as positive predictors for recurrent UTI (p

Polymyxin B Nephrotoxicity: From Organ to Cell Damage

PubMed Central

Pessoa, Edson Andrade

2016-01-01

Polymyxins have a long history of dose-limiting toxicity, but the underlying mechanism of polymyxin B-induced nephrotoxicity is unclear. This study investigated the link between the nephrotoxic effects of polymyxin B on renal metabolic functions and mitochondrial morphology in rats and on the structural integrity of LLC-PK1 cells. Fifteen Wistar rats were divided into two groups: Saline group, rats received 3 mL/kg of 0.9% NaCl intraperitoneally (i.p.) once a day for 5 days; Polymyxin B group, rats received 4 mg/kg/day of polymyxin B i.p. once a day for 5 days. Renal function, renal hemodynamics, oxidative stress, mitochondrial injury and histological characteristics were assessed. Cell membrane damage was evaluated via lactate dehydrogenase and nitric oxide levels, cell viability, and apoptosis in cells exposed to 12.5 μM, 75 μM and 375 μM polymyxin B. Polymyxin B was immunolocated using Lissamine rhodamine-polymyxin B in LLC-PK1 cells. Polymyxin B administration in rats reduced creatinine clearance and increased renal vascular resistance and oxidative damage. Mitochondrial damage was confirmed by electron microscopy and cytosolic localization of cytochrome c. Histological analysis revealed tubular dilatation and necrosis in the renal cortex. The reduction in cell viability and the increase in apoptosis, lactate dehydrogenase levels and nitric oxide levels confirmed the cytotoxicity of polymyxin B. The incubation of LLC-PK1 cells resulted in mitochondrial localization of polymyxin B. This study demonstrates that polymyxin B nephrotoxicity is characterized by mitochondrial dysfunction and free radical generation in both LLC-PK1 cells and rat kidneys. These data also provide support for clinical studies on the side effects of polymyxin B. PMID:27532263

Urinary creatinine to serum creatinine ratio and renal failure index in dogs infected with Babesia canis.

PubMed

Zygner, Wojciech; Gójska-Zygner, Olga; Wesołowska, Agnieszka; Wędrychowicz, Halina

2013-09-01

Urinary creatinine to serum creatinine (UCr/SCr) ratio and renal failure index (RFI) are useful indices of renal damage. Both UCr/SCr ratio and RFI are used in differentiation between prerenal azotaemia and acute tubular necrosis. In this work the authors calculated the UCr/SCr ratio and RFI in dogs infected with Babesia canis and the values of these indices in azotaemic dogs infected with the parasite. The results of this study showed significantly lower UCr/SCr ratio in dogs infected with B. canis than in healthy dogs. Moreover, in azotaemic dogs infected with B. canis the UCr/SCr ratio was significantly lower and the RFI was significantly higher than in non-azotaemic dogs infected with B. canis. The calculated correlation between RFI and duration of the disease before diagnosis and treatment was high, positive and statistically significant (r = 0.89, p < 0.001). The results of this study showed that during the course of canine babesiosis caused by B. canis in Poland acute tubular necrosis may develop.

Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery.

PubMed

Basu, Rajit K; Wong, Hector R; Krawczeski, Catherine D; Wheeler, Derek S; Manning, Peter B; Chawla, Lakhmir S; Devarajan, Prasad; Goldstein, Stuart L

2014-12-30

Increases in serum creatinine (ΔSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication. This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI. Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (≥100% ΔSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline ≤48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to ΔSCr increases of ≥50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values [Corrected]. Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than ΔSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL-/pCysC+ composite was superior to ΔSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than ΔSCr strata. Composites of functional and tubular damage biomarkers are superior to ΔSCr for predicting discrete characteristics of AKI. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Atgl gene deletion predisposes to proximal tubule damage by impairing the fatty acid metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Wen; Zhang, Qiong; Cheng, Shiwu

Fibrosis is the final common pathway of chronic kidney disease (CKD). Normal lipid metabolism is integral to renal physiology, and disturbances of renal lipid metabolism are increasingly being linked with CKD, including the fibrosis. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis. In the present study, we used Atgl{sup −/−} mice to investigate whether ATGL played a role in the regulation of proximal convoluted tubule (PCT) lipid metabolism and renal fibrosis development. ATGL deficiency led to lipid vacuolation of PCT and tubulointerstitial fibrosis, accompanied by massive albuminuria and decreased creatinine clearance rate (Ccr). In vitro experiments indicated that inhibitionmore » of ATGL in proximal tubular cell line HK-2 promoted intracellular lipid deposition, reactive oxygen species (ROS) accumulation and cell apoptosis. Both in vitro and in vivo experiments showed that ATGL inhibition decreased the renal peroxisome proliferator-activated receptorα(PPARα) expression, which implied the suppressed lipid metabolism. The antioxidant N-acetylcysteine (NAC) could partially reverse the effect of ROS accumulation and cell apoptosis, but could not restore the PPARαdecrease. These data raise the possibility that ATGL deficiency could impair the renal fatty acid metabolism though inhibiting PPARαexpression, which may lead to lipid deposition and cell apoptosis of PCT, and finally contribute to the renal fibrosis and dysfunction. - Highlights: • Atgl{sup −/−} mice develop tubulointerstitial damage and renal dysfunction. • ATGL deficiency results in lipid accumulation and apoptosis of proximal tubular cells. • ROS scavenger alleviates the ATGL-knockdown mediated lipid accumulation and apoptosis. • PPARαdown-regulation is the reason of ROS elevating in ATGL-knockdown HK-2 cells.« less

Damage evaluation of fiber reinforced plastic-confined circular concrete-filled steel tubular columns under cyclic loading using the acoustic emission technique

NASA Astrophysics Data System (ADS)

Li, Dongsheng; Du, Fangzhu; Ou, Jinping

2017-03-01

Glass-fiber reinforced plastic (GFRP)-confined circular concrete-filled steel tubular (CCFT) columns comprise of concrete, steel, and GFRP and show complex failure mechanics under cyclic loading. This paper investigated the failure mechanism and damage evolution of GFRP-CCFT columns by performing uniaxial cyclic loading tests that were monitored using the acoustic emission (AE) technique. Characteristic AE parameters were obtained during the damage evolution of GFRP-CCFT columns. Based on the relationship between the loading curve and these parameters, the damage evolution of GFRP-CCFT columns was classified into three stages that represented different damage degrees. Damage evolution and failure mode were investigated by analyzing the b-value and the ratio of rise time to waveform amplitude and average frequency. The damage severity of GFRP-CCFT columns were quantitatively estimated according to the modified index of damage and NDIS-2421 damage assessment criteria corresponding to each loading step. The proposed method can explain the damage evolution and failure mechanism for GFRP-CCFT columns and provide critical warning information for composite structures.

Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury.

PubMed

Reichetzeder, Christoph; von Websky, Karoline; Tsuprykov, Oleg; Mohagheghi Samarin, Azadeh; Falke, Luise Gabriele; Dwi Putra, Sulistyo Emantoko; Hasan, Ahmed Abdallah; Antonenko, Viktoriia; Curato, Caterina; Rippmann, Jörg; Klein, Thomas; Hocher, Berthold

2017-07-01

Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. IRI was induced in uninephrectomized male rats by renal artery clamping for 30 min. The sham group was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p.o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg·kg -1 ·day -1 ), vildagliptin (8 mg·kg -1 ·day -1 ) and sitagliptin (30 mg·kg -1 ·day -1 ). An additional group received sitagliptin until study end (before IRI: 30 mg·kg -1 ·day -1 ; after IRI: 15 mg·kg -1 ·day -1 ). Plasma-active glucagon-like peptide type 1 (GLP-1) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP-1 plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage. © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Effects of a Single Dose of Parecoxib on Inflammatory Response and Ischemic Tubular Injury Caused by Hemorrhagic Shock in Rats.

PubMed

Takaku, Mariana; da Silva, Andre Carnevali; Iritsu, Nathalie Izumi; Vianna, Pedro Thadeu Galvao; Castiglia, Yara Marcondes Machado

2018-01-01

Parecoxib, a selective COX-2 inhibitor, is used to improve analgesia in postoperative procedures. Here we evaluated whether pretreatment with a single dose of parecoxib affects the function, cell injury, and inflammatory response of the kidney of rats subjected to acute hemorrhage. Inflammatory response was determined according to serum and renal tissue cytokine levels (IL-1 α , IL-1 β , IL-6, IL-10, and TNF- α ). Forty-four adult Wistar rats anesthetized with sevoflurane were randomized into four groups: placebo/no hemorrhage (Plc/NH); parecoxib/no hemorrhage (Pcx/NH); placebo/hemorrhage (Plc/H); and parecoxib/hemorrhage (Pcx/H). Pcx groups received a single dose of intravenous parecoxib while Plc groups received a single dose of placebo (isotonic saline). Animals in hemorrhage groups underwent bleeding of 30% of blood volume. Renal function and renal histology were then evaluated. Plc/H showed the highest serum levels of cytokines, suggesting that pretreatment with parecoxib reduced the inflammatory response in rats subjected to hemorrhage. No difference in tissue cytokine levels between groups was observed. Plc/H showed higher percentage of tubular dilation and degeneration, indicating that parecoxib inhibited tubular injury resulting from renal hypoperfusion. Our findings indicate that pretreatment with a single dose of parecoxib reduced the inflammatory response and tubular renal injury without altering renal function in rats undergoing acute hemorrhage.

GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure.

PubMed

Pons, Marianne; Koniaris, Leonidas G; Moe, Sharon M; Gutierrez, Juan C; Esquela-Kerscher, Aurora; Zimmers, Teresa A

2018-05-03

GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases. In vitro renal cell lines, genetic, and murine in vivo renal injury models were examined. Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely after 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, or unilateral ureteric obstruction. Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis, and expression of fibrosis-associated genes both at baseline and after unilateral ureteric obstruction compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted epithelial-to-mesenchymal transition of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner. Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury

PubMed Central

Kim, Mihwa; Ham, Ahrom; Kim, Joo Yun; Brown, Kevin M.; D’Agati, Vivette D.; Lee, H. Thomas

2013-01-01

The volatile anesthetic isoflurane protects against renal ischemia and reperfusion injury by releasing renal tubular TGF-β1. Since adenosine is a powerful cytoprotective molecule, we tested whether TGF-β1 generated by isoflurane induces renal tubular ecto-5′-nucleotidase (CD73) and adenosine to protect against renal ischemia and reperfusion injury. Isoflurane induced new CD73 synthesis and increased adenosine generation in cultured kidney proximal tubule cells and in mouse kidney. Moreover, a TGF-β1 neutralizing antibody prevented isoflurane-mediated induction of CD73 activity. Mice anesthetized with isoflurane after renal ischemia and reperfusion had significantly reduced plasma creatinine and decreased renal tubular necrosis, neutrophil infiltration and apoptosis compared to pentobarbital-anesthetized mice. Isoflurane failed to protect against renal ischemia and reperfusion injury in CD73 deficient mice, in mice pretreated with a selective CD73 inhibitor or mice treated with an adenosine receptor antagonist. The TGF-β1 neutralizing antibody or the CD73 inhibitor attenuated isoflurane-mediated protection against HK-2 cell apoptosis. Thus, isoflurane causes TGF-β1-dependent induction of renal tubular CD73 and adenosine generation to protect against renal ischemia and reperfusion injury. Modulation of this pathway may have important therapeutic implications to reduce morbidity and mortality arising from ischemic acute kidney injury. PMID:23423261

Renal Control of Calcium, Phosphate, and Magnesium Homeostasis

PubMed Central

Chonchol, Michel; Levi, Moshe

2015-01-01

Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys. PMID:25287933

Comparison of para-aminophenol cytotoxicity in rat renal epithelial cells and hepatocytes.

PubMed

Li, Ying; Bentzley, Catherine M; Tarloff, Joan B

2005-04-01

Several chemicals, including para-aminophenol (PAP), produce kidney damage in the absence of hepatic damage. Selective nephrotoxicity may be related to the ability of the kidney to reabsorb filtered water, thereby raising the intraluminal concentration of toxicants and exposing tubular epithelial cells to higher concentrations than would be present in other tissues. The present experiments tested the hypothesis that hepatocytes and renal epithelial cells exposed to equivalent concentrations of PAP would be equally susceptible to toxicity. Hepatocytes and renal epithelial cells were prepared by collagenase digestion of tissues obtained from female Sprague-Dawley rats. Toxicity was monitored using trypan blue exclusion, oxygen consumption and ATP content. We measured the rate of PAP clearance and formation of PAP-glutathione conjugate by HPLC. We found that renal epithelial cells accumulated trypan blue and showed declines in oxygen consumption and ATP content at significantly lower concentrations of PAP and at earlier time points than hepatocytes. The half-life of PAP in hepatocyte incubations was significantly shorter (0.71+/-0.07 h) than in renal epithelial cell incubations (1.33+/-0.23 h), suggesting that renal epithelial cells were exposed to PAP for longer time periods than hepatocytes. Renal epithelial cells formed significantly less glutathione conjugates of PAP (PAP-SG) than did hepatocytes, consistent with less efficient detoxification of reactive PAP intermediates by renal epithelial cells. Finally, hepatocytes contained significant more reduced glutathione (NPSH) than did renal epithelial cells, possibly explaining the enhanced formation of PAP-SG by this cell population. In conclusion, our data indicates that renal epithelial cells are intrinsically more susceptible to PAP cytotoxicity than are hepatocytes. This enhanced cytotoxicity may be due to longer exposure to PAP and/or reduced detoxification of reactive intermediates due to lower concentrations

Osthole ameliorates renal ischemia-reperfusion injury in rats.

PubMed

Zheng, Yi; Lu, Min; Ma, Lulin; Zhang, Shudong; Qiu, Min; Wang, Yunpeng

2013-07-01

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms underlying I/R injury involve oxidative stress and apoptosis. Osthole, a natural coumarin derivative, has been reported to possess antioxidant and antiapoptotic activities. This study aimed to investigate the potential effects of osthole on renal I/R injury in an in vivo rat model. We induced renal I/R injury by clamping the left renal artery for 45 min followed by reperfusion, along with a contralateral nephrectomy. We randomly assigned 54 rats to three groups (18 rats/group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle (40 mg/kg) 30 min before renal ischemia. We harvested serum and kidneys at 1, 6, and 24 h after reperfusion. Renal function and histological changes were assessed. We also determined markers of oxidative stress and cell apoptosis in kidneys. Osthole treatment significantly attenuated renal dysfunction and histologic damage induced by I/R injury. The I/R-induced elevation in kidney malondialdehyde level decreased, whereas reduced kidney superoxide dismutase and catalase activities were markedly increased. Moreover, osthole-treated rats had a dramatic decrease in apoptotic tubular cells, along with a decrease in caspase-3 and an increase in the Bcl-2/Bax ratio. Osthole treatment protects murine kidney from renal I/R injury by suppressing oxidative stress and cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model.

PubMed

Wang, Diping; Warner, Gina M; Yin, Ping; Knudsen, Bruce E; Cheng, Jingfei; Butters, Kim A; Lien, Karen R; Gray, Catherine E; Garovic, Vesna D; Lerman, Lilach O; Textor, Stephen C; Nath, Karl A; Simari, Robert D; Grande, Joseph P

2013-04-01

Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude that p38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

Renal effects of continuous negative pressure breathing

NASA Technical Reports Server (NTRS)

Kinney, M. J.

1975-01-01

Continuous negative pressure breathing (CNPB) was utilized to simulate the thoracic vascular distension of zero G in 11 anesthetized rats. The animals underwent renal clearance and micropuncture renal nephron studies before, during, and after CNPB. Four rats were pretreated with a high salt diet and I-M desoxycorticosterone (DOCA) in excess. None of these rats diuresed with CNPB. In contrast, five of the seven remaining rats increased the fraction of the filtered sodium excreted and their urinary flow rate. Potassium excretion increased. End proximal tubular fluid specimen's TF/P inulin ratios were unchanged. Whole kidney and single nephron glomerular filtration rates fell 10%. CNPB, a mechanism for atrial distension, appears to cause in the rat a decrease in distal tubular sodium and water reabsorption. Exogenous mineral-corticoid prevents the diuresis, saluresis, and kaluresis. The adequacy of other nonatrial volume control mechanisms in regulating renal salt and water conservation in opposition to the studied atrial-renal (Henry-Gauer) reflex of thoracic vascular distension is confirmed.

Cisplatin-induced cytotoxicity in BSO-exposed renal proximal tubular epithelial cells: sex, age, and species.

PubMed

Lu, Yongke; Kawashima, Akira; Horii, Ikuo; Zhong, Laifu

2005-01-01

Cisplatin (CP)-induced kidney damage and effects of DL-buthionine-(S,R)-sulfoximine (BSO) on it are species- and age-different. It remains unclear whether CP-induced cytotoxicity in renal proximal tubular epithelial cells (RTEC), the main target cells of CP, is also species- and age-different; and whether CP-induced cytotoxicity varies with the difference in age and species, if any, is one of the questions. In the present study, the effects of BSO on CP-induced cytotoxicity in primary cultures of RTEC isolated from monkeys and different age and sex rats were studied. The RTEC were isolated from 3-week-old, 2-month-old, or 5-month-old rats, and 6-8 year-old monkeys. After subculturing, RTEC was inoculated into type I collagen-coated 96-well culture plates; after preincubation, 40 microM BSO was added, 16 hours later, varying concentrations of CP were added. At that time, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays were performed to test cell viability. The concentrations of CP that inhibited 50% cell growth (IC50) of RTEC from rats and monkeys were 1.11 and 3.03 mM at 8 hours, and 0.51 and 1.24 mM at 24 hours, respectively. The BSO made the IC50s of RTEC from rats and monkeys lower, down to 0.07 and 0.48 mM at 8 hours, and 0.02 and 0.11 mM at 24 hours, respectively. The IC50s of RTEC from different sex and age rats were almost same. These results suggested that CP-induced cytotoxicity was concentration- and time-dependent, with species-dependent differences, rat RTEC were more susceptible to CP than monkey RTEC, rat RTEC were more dependent on glutathione (GSH) during the stress state were than monkey cells; CP-induced cytotoxicity was without sex- and age-dependent differences in rat RTEC.

Renal rickets-practical approach

PubMed Central

Sahay, Manisha; Sahay, Rakesh

2013-01-01

Rickets/osteomalacia is an important problem in a tropical country. Many cases are due to poor vitamin D intake or calcium deficient diets and can be corrected by administration of calcium and vitamin D. However, some cases are refractory to vitamin D therapy and are related to renal defects. These include rickets of renal tubular acidosis (RTA), hypophosphatemic rickets, and vitamin D dependent rickets (VDDR). The latter is due to impaired action of 1α-hydroxylase in renal tubule. These varieties need proper diagnosis and specific treatment. PMID:24251212

Spermidine rescues proximal tubular cells from oxidative stress and necrosis after ischemic acute kidney injury.

PubMed

Kim, Jinu

2017-10-01

Kidney ischemia and reperfusion injury (IRI) is associated with a high mortality rate, which is attributed to tubular oxidative stress and necrosis; however, an effective approach to limit IRI remains elusive. Spermidine, a naturally occurring polyamine, protects yeast cells against aging through the inhibition of oxidative stress and necrosis. In the present study, spermidine supplementation markedly attenuated increases in plasma creatinine concentration and tubular injury score after IRI. In addition, exogenous spermidine potently inhibited oxidative stress, especially lipid peroxidation after IRI in kidneys and exposure to hydrogen peroxide in kidney proximal tubular cells, suppressing plasma membrane disruption and necrosis. Consistent with spermidine supplementation, upregulation of ornithine decarboxylase (ODC) in human kidney proximal tubular cells significantly diminished lipid peroxidation and necrosis induced by hydrogen peroxide-induced injury. Conversely, ODC deficiency significantly enhanced lipid peroxidation and necrosis after exposure to hydrogen peroxide. Finally, small interfering RNA-mediated ODC inhibition induced functional and histological damage in kidneys as well as it increased lipid hydroperoxide levels after IRI. In conclusion, these data suggest that spermidine level determines kidney proximal tubular damage through oxidative stress and necrosis induced by IRI, and this finding provides a novel target for prevention of tubular damage induced by IRI.

Tubular and genetic disorders associated with kidney stones.

PubMed

Mohebbi, Nilufar; Ferraro, Pietro Manuel; Gambaro, Giovanni; Unwin, Robert

2017-02-01

This concise review summarizes our current understanding and the recent developments in genetics and related renal tubular disorders that have been linked with, or have been shown to be causal in, renal stone disease. The aim is to provide a readily accessible quick and easy update for urologists, nephrologists and endocrine or metabolic physicians whose practice involves the diagnosis and management of nephrolithiasis. An important message is to always consider a seemingly rare, and usually genetic, cause of kidney stones, since some of these are emerging as more common than originally thought, especially in adult clinical practice in which a family history of stones is a common finding.

Effect of novel vitamin D receptor activator paricalcitol on renal ischaemia/reperfusion injury in rats

PubMed Central

Huddam, B; Haberal, N; Koçak, G; Ortabozkoyun, L; Şenes, M; Akdoğan, MF; Denizli, N; Duranay, M

2013-01-01

Introduction Despite the developments in modern medicine, acute renal injury is still a challenging and common health problem. It is well known that ischaemia and reperfusion takes place in pathological mechanisms. Efforts to clarify the pathophysiology and interventions to improve outcomes are essential. Our study aimed to investigate whether the prophylactic use of paricalcitol is beneficial in renal ischaemia/reperfusion (I/R) injury. Methods Twenty-four Wistar albino rats were assigned randomly to four groups. Right nephrectomies were performed at the time of renal arterial clamping. Sham surgery was performed on the rats in group 1. For the rats in group 2, the left renal artery was clamped for 45 minutes. The rats in group 3 received paricalcitol for seven days (0.2µg/kg/day); following this, a right nephrectomy and left renal arterial clamping were not performed. The rats in group 4 received paricalcitol for seven days (0.2µg/ kg/day); following this, a right nephrectomy and left renal arterial clamping for 45 minutes were performed. Tissue thiobarbituric acid reactive substances (TBARS), superoxide dismutase, sulfhydryl groups as well as nitric oxide metabolites, serum urea and creatinine levels were measured for all four groups. Results In group 4, there were some improvements in terms of TBARS, nitrite, nitrate, superoxide dismutase and creatinine levels. In the histopathological evaluation, paricalcitol therapy improved tubular necrosis and medullar congestion but there was no significant difference in terms of tubular cell swelling, cellular vacuolisation or general damage. Immunohistopathological examination revealed lower scores for vascular endothelial growth factor in the group 4 rats than in group 2. Conclusions Paricalcitol therapy improved renal I/R injury in terms of serum and histopathological parameters. These potential beneficial effects need to be further investigated. PMID:24112495

The Piezo Actuator-Driven Pulsed Water Jet System for Minimizing Renal Damage after Off-Clamp Laparoscopic Partial Nephrectomy.

PubMed

Kamiyama, Yoshihiro; Yamashita, Shinichi; Nakagawa, Atsuhiro; Fujii, Shinji; Mitsuzuka, Koji; Kaiho, Yasuhiro; Ito, Akihiro; Abe, Takaaki; Tominaga, Teiji; Arai, Yoichi

2017-09-01

In the setting of partial nephrectomy (PN) for renal cell carcinoma, postoperative renal dysfunction might be caused by surgical procedure. The aim of this study was to clarify the technical safety and renal damage after off-clamp laparoscopic PN (LPN) with a piezo actuator-driven pulsed water jet (ADPJ) system. Eight swine underwent off-clamp LPN with this surgical device, while off-clamp open PN was also performed with radio knife or soft coagulation. The length of the removed kidney was 40 mm, and the renal parenchyma was dissected until the renal calyx became clearly visible. The degree of renal degeneration from the resection surface was compared by Hematoxylin-Eosin staining and immunostaining for 1-methyladenosine, a sensitive marker for the ischemic tissue damage. The mRNA levels of neutrophil gelatinase-associated lipocalin (Ngal), a biomarker for acute kidney injury, were measured by quantitative real-time PCR. Off-clamp LPN with ADPJ system was successfully performed while preserving fine blood vessels and the renal calix with little bleeding. In contrast to other devices, the resection surface obtained with the ADPJ system showed only marginal degree of ischemic changes. Indeed, the expression level of Ngal mRNA was lower in the resection surface obtained with the ADPJ system than that with soft coagulation (p = 0.02). Furthermore, using the excised specimens of renal cell carcinoma, we measured the breaking strength at each site of the human kidney, suggesting the applicability of this ADPJ to clinical trials. In conclusion, off-clamp LPN with the ADPJ system could be safely performed with attenuated renal damage.

Surface heat shock protein 90 serves as a potential receptor for calcium oxalate crystal on apical membrane of renal tubular epithelial cells.

PubMed

Fong-Ngern, Kedsarin; Sueksakit, Kanyarat; Thongboonkerd, Visith

2016-07-01

Adhesion of calcium oxalate monohydrate (COM) crystals on renal tubular epithelial cells is a crucial step in kidney stone formation. Finding potential crystal receptors on the apical membrane of the cells may lead to a novel approach to prevent kidney stone disease. Our previous study identified a large number of crystal-binding proteins on the apical membrane of MDCK cells. However, their functional role as potential crystal receptors had not been validated. The present study aimed to address the potential role of heat shock protein 90 (HSP90) as a COM crystal receptor. The apical membrane was isolated from polarized MDCK cells by the peeling method and recovered proteins were incubated with COM crystals. Western blot analysis confirmed the presence of HSP90 in the apical membrane and the crystal-bound fraction. Immunofluorescence staining without permeabilization and laser-scanning confocal microscopy confirmed the surface HSP90 expression on the apical membrane of the intact cells. Crystal adhesion assay showed that blocking surface HSP90 by specific anti-HSP90 antibody and knockdown of HSP90 by small interfering RNA (siRNA) dramatically reduced crystal binding on the apical surface of MDCK cells (by approximately 1/2 and 2/3, respectively). Additionally, crystal internalization assay revealed the presence of HSP90 on the membrane of endocytic vesicle containing the internalized COM crystal. Moreover, pretreatment of MDCK cells with anti-HSP90 antibody significantly reduced crystal internalization (by approximately 1/3). Taken together, our data indicate that HSP90 serves as a potential receptor for COM crystals on the apical membrane of renal tubular epithelial cells and is involved in endocytosis/internalization of the crystals into the cells.

Suppression of BMP-7 by histone deacetylase 2 promoted apoptosis of renal tubular epithelial cells in acute kidney injury

PubMed Central

Ma, Taotao; Huang, Cheng; Xu, Qingqing; Yang, Yang; Liu, Yaru; Meng, Xiaoming; Li, Jun; Ye, Min; Liang, Hong

2017-01-01

Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by histone deacetylase (HDAC) inhibitors via epigenetic modification to enhance bone morphogenetic protein 7 (BMP-7) expression. Cisplatin upregulated the activity of HDAC2 in the kidney. Inhibition of HDAC with clinically used trichostatin A (TSA) or valproic acid (VPA) suppressed cisplatin-induced kidney injury and epithelial cell apoptosis. Overexpression of HDAC2 promotes CP-treated tubular epithelium cells apoptosis. Chromatin immunoprecipitation assay clearly detected HDAC2 assosiation with BMP-7 promoter. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by TSA or VPA in vivo and in vitro. Interestingly, administration of recombinant BMP-7 (rhBMP-7) reduced cisplatin-induced kidney dysfunction. Moreover, BMP-7 treatment suppressed epithelial cell apoptosis and small interfering RNA-based knockdown of BMP-7 expression abolished HDAC inhibitors suppression of epithelial cell apoptosis in vitro. Results of current study indicated that TSA or VPA inhibited apoptosis of renal tubular epithelial cells via promoting the level of BMP-7 epigenetically through targeting HDAC2. Hence, HDAC inhibitors could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity. PMID:29072686

Azilsartan improves glycemic status and reduces kidney damage in zucker diabetic fatty rats.

PubMed

Hye Khan, Md Abdul; Neckář, Jan; Haines, Jasmine; Imig, John D

2014-08-01

Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, demonstrates antihypertensive and organ protective effects in hypertension. We investigated the efficacy of AZL-M to ameliorate metabolic syndrome and kidney damage associated with type 2 diabetes using Zucker diabetic fatty (ZDF) rats. ZDF rats were treated with vehicle or AZL-M for 8 weeks. Zucker diabetic lean (ZDL) rats were used as controls. Urine and plasma samples were collected for biochemical analysis, and kidney tissues were used for histopathological and immunohistopathological examination at the end of the 8-week protocol. ZDF rats were diabetic with hyperglycemia and impaired glucose tolerance, and AZL-M ameliorated the diabetic phenotype. ZDF rats were hypertensive compared with ZDL rats (181±6 vs. 129±7mm Hg), and AZL-M decreased blood pressure in ZDF rats (116±7mm Hg). In ZDF rats, there was marked renal damage with elevated proteinuria, albuminuria, nephrinuria, 2-4-fold higher tubular cast formation, and glomerular injury compared with ZDL rats. AZL-M treatment reduced renal damage in ZDF rats. ZDF rats demonstrated renal inflammation and oxidative stress with elevated urinary monocyte chemoattractant protein 1 excretion, renal infiltration of macrophages, and elevated kidney malondialdehyde levels. AZL-M reduced oxidative stress and inflammation in ZDF rats. Overall, we demonstrate that AZL-M attenuates kidney damage in type 2 diabetes. We further demonstrate that anti-inflammatory and antioxidative activities of AZL-M contribute to its kidney protective action. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Total mercury levels in hair, toenail, and urine among women free from occupational exposure and their relations to renal tubular function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohno, Tomoko; Sakamoto, Mineshi; Kurosawa, Tomoko

2007-02-15

To investigate the relations among total mercury levels in hair, toenail, and urine, together with potential effects of methylmercury intake on renal tubular function, we determined their levels, and urinary N-acetyl-{beta}-d-glucosaminidase activity (NAG) and {alpha}{sub 1}-microglobulin (AMG) in 59 women free from occupational exposures, and estimated daily mercury intakes from fish and other seafood using a food frequency questionnaire. Mercury levels (mean+/-SD) in the women were 1.51+/-0.91{mu}g/g in hair, 0.59+/-0.32{mu}g/g in toenail, and 0.86+/-0.66{mu}g/g creatinine in urine; and, there were positive correlations among them (P<0.001). The daily mercury intake of 9.15+/-7.84{mu}g/day was significantly correlated with total mercury levels in hair,more » toenail, and urine (r=0.551, 0.537, and 0.604, P<0.001). Among the women, the NAG and AMG were positively correlated with both the daily mercury intake and mercury levels in hair, toenail, and urine (P<0.01); and, these relations were almost similar when using multiple regression analysis to adjust for possible confounders such as urinary cadmium (0.47+/-0.28{mu}g/g creatinine) and smoking status. In conclusion, mercury resulting from fish consumption can explain total mercury levels in hair, toenail, and urine to some degree (about 30%), partly through the degradation into the inorganic form, and it may confound the renal tubular effect of other nephrotoxic agents. Also, the following equation may be applicable to the population neither with dental amalgam fillings nor with occupational exposures: [hair mercury ({mu}g/g)]=2.44x[toenail mercury ({mu}g/g)].« less

Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats.

PubMed

Hirata, Michinori; Tashiro, Yoshihito; Aizawa, Ken; Kawasaki, Ryohei; Shimonaka, Yasushi; Endo, Koichi

2015-12-01

The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules. © 2015 Chugai Pharmaceutical Co., Ltd. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Reno-protective effects of propolis on gentamicin-induced acute renal toxicity in swiss albino mice.

PubMed

Aldahmash, Badr Abdullah; El-Nagar, Doaa Mohamed; Ibrahim, Khalid Elfakki

Kidney is a vital organ which plays an important and irreplaceable role in detoxification and removal of xenobiotics. And therefore is vulnerable to develop various forms of injuries. Hence, making it immensely important to search for natural reno-protective compounds. This study therefore, aims to evaluate the reno-protective properties of propolis against gentamicin induced renal toxicity in mice. Three groups of 10 male mice each were used for this study. First group served as control, the second group (Gm group) was administered orally 80mg/kg body weight gentamicin for 7 days, and the third group (GmP group) was administered same dose of gentamicin with propolis (500mg/kg body weight) for 7 days. Various parameters were used to study the renal toxicity. Gentamicin caused significant renal damage as evident by the rise in BUN levels, diminished glomeruli hypocellularity, moderately dilated tubules, and mild loss of brush border, severe infiltration, extensive tubular degeneration and presence of tubular cast. Histochemistry results show presence of collagen and reticular fibres. Immunohistochemical reactions show kidney injury (Kim-1 gene-expression), oxidative stress (MDA gene-expression), and an increase in apoptosis (caspase-3 gene-expression). Co-administration of propolis with gentamicin showed significant decrease in BUN levels, appearance of healthy glomeruli with normal cellularity, reduction of tubular injury, decrease of collagen and reticular fibres deposition, reduction of apoptosis, kidney injury and oxidative stress. Results presented in this study clearly show the reno-protective role of propolis against gentamicin-induced toxicity on mice kidney. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Factors associated with cardiovascular target organ damage in children after renal transplantation.

PubMed

Borchert-Mörlins, Bianca; Thurn, Daniela; Schmidt, Bernhard M W; Büscher, Anja K; Oh, Jun; Kier, Tanja; Bauer, Elena; Baig, Sabrina; Kanzelmeyer, Nele; Kemper, Markus J; Büscher, Rainer; Melk, Anette

2017-11-01

Cardiovascular disease is the second-most common cause of death in pediatric renal transplant recipients. The aim of this study was to evaluate subclinical cardiovascular target organ damage defined as the presence of arterio- and atherosclerotic lesions and cardiac remodeling and to analyze contributing risk factors in a large cohort of children after renal transplantation (RT). A total of 109 children aged 13.1 ± 3.3 years who had undergone RT at one of three German transplant centers were enrolled in this study. Patients had been transplanted a mean of 5.5 (±4.0) years prior to being enrolled in the study. Anthropometric data, laboratory values and office- and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated. Cardiovascular target organ damage was determined through non-invasive measurements of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) and left ventricular mass (LVM). Elevated PWV or IMT values were detected in 22 and 58% of patients, respectively. Left ventricular hypertrophy was found in as many as 43% of patients. The prevalence of uncontrolled or untreated hypertension was 41%, of which 16% of cases were only detected by ABPM measurements. In the multivariable analysis, higher diastolic blood pressure, everolimus intake and lower estimated glomerular filtration rate were independently associated with high PWV. Higher systolic blood pressure and body mass index were associated with elevated LVM. Our results showed an alarming burden of cardiovascular subclinical organ damage in children after RT. Hypertension, obesity, immunosuppressive regimen and renal function emerged as independent risk factors of organ damage. Whereas the latter is not modifiable, the results of our study strongly indicate that the management of children after RT should focus on the control of blood pressure and weight.

[Effect of Cordyceps sinensis on the expression of HIF-1α and NGAL in rats with renal ischemia-reperfusion injury].

PubMed

Yu, Honglei; Zhou, Qiaoling; Huang, Renfa; Yuan, Mingxia; Ao, Xiang; Yang, Jinghua

2012-01-01

the pathological changes. Renal I/R injury in rats can lead to pathological changes in renal tubular epithelial cells and renal interstitial damage, which are consistent with the pathological features of acute kidney injury (AKI).The level of urinary NAGL increases after the I/R, and positively correlates with the level of urinary NAG and pathological changes, suggesting that urinary NGAL may serve as a urinary biomarker for specific detection of tubular injury in AKI. C. sinensis can attenuate the renal I/ R-induced AKI. Its mechanism may be associated with up-regulating the expression of HIF-1α and down-regulating the expression of NGAL in the kidney tissues.

Renal control of calcium, phosphate, and magnesium homeostasis.

PubMed

Blaine, Judith; Chonchol, Michel; Levi, Moshe

2015-07-07

Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys. Copyright © 2015 by the American Society of Nephrology.

Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome.

PubMed

Faqeih, Eissa; Al-Akash, Samhar I; Sakati, Nadia; Teebi, Prof Ahmad S

2007-09-01

We report on four siblings (three males, one female) born to first cousin Arab parents with the constellation of distal renal tubular acidosis (RTA), small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features. They presented with early developmental delay with subsequent severe mental, behavioral and social impairment and autistic-like features. Their facial features are unique with prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule. All had proteinuria, hypercalciuria, hypercalcemia, and normal anion-gap metabolic acidosis. Renal ultrasound examinations revealed small kidneys, with varying degrees of hyperechogenicity and nephrocalcinosis. Additional findings included dilated ventricles and cerebral demyelination on brain imaging studies. Other than distal RTA, common causes of nephrocalcinosis were excluded. The constellation of features in this family currently likely represents a possibly new autosomal recessive syndrome providing further evidence of heterogeneity of nephrocalcinosis syndromes. Copyright 2007 Wiley-Liss, Inc.

DNA damage response in nephrotoxic and ischemic kidney injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan, Mingjuan; Tang, Chengyuan

DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore reliesmore » on a thorough elucidation of the DDR pathways in various forms of AKI.« less

Attenuation of Cisplatin-Induced Renal Injury by Inhibition of Soluble Epoxide Hydrolase Involves Nuclear Factor κB Signaling

PubMed Central

Liu, Yingmei; Webb, Heather K.; Fukushima, Hisayo; Micheli, Janine; Markova, Svetlana; Olson, Jean L.

2012-01-01

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(−/−) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(−/−) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy. PMID:22414856

The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.

PubMed

Seleznik, Gitta; Seeger, Harald; Bauer, Judith; Fu, Kai; Czerkowicz, Julie; Papandile, Adrian; Poreci, Uriana; Rabah, Dania; Ranger, Ann; Cohen, Clemens D; Lindenmeyer, Maja; Chen, Jin; Edenhofer, Ilka; Anders, Hans J; Lech, Maciej; Wüthrich, Rudolf P; Ruddle, Nancy H; Moeller, Marcus J; Kozakowski, Nicolas; Regele, Heinz; Browning, Jeffrey L; Heikenwalder, Mathias; Segerer, Stephan

2016-01-01

Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases. Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats.

PubMed

Vogelaar, Pieter C; Roorda, Maurits; de Vrij, Edwin L; Houwertjes, Martin C; Goris, Maaike; Bouma, Hjalmar; van der Graaf, Adrianus C; Krenning, Guido; Henning, Robert H

2018-04-11

Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 µg/kg/h) undergoing H/R at 15°C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed. H/R injury in vitro lowered cell viability by 94 ± 1%, which was counteracted dose-dependently by multiple 6-hydroxychomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 5'-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols

Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound.

PubMed

Hossain, Md Murad; Selzo, Mallory R; Hinson, Robert M; Baggesen, Leslie M; Detwiler, Randal K; Chong, Wui K; Burke, Lauren M; Caughey, Melissa C; Fisher, Melrose W; Whitehead, Sonya B; Gallippi, Caterina M

2018-05-10

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

PubMed Central

Maicas, Nuria; van der Vlag, Johan; Bublitz, Janin; Florquin, Sandrine; Bakker-van Bebber, Marinka; Dinarello, Charles A.; Verweij, Vivienne; Masereeuw, Roos; Joosten, Leo A.

2017-01-01

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions. PMID:28235038

Apoptosis of rat renal cells by organophosphate pesticide, quinalphos: Ultrastructural study.

PubMed

Eid, Refaat A

2017-01-01

Quinalphos or Ekalux, an organophosphate pesticide, is used in controlling the pests of a variety of crops. Quinalphos was studied on male Sprague-Dawley albino rats. The acute po LD50 of technical Ekalux was 19.95 mg/kg in males. Ekalux, produced several pathological changes in the kidney. A glomerulus demonstrated capillary lumina occluded by degenerated cellular debris. Basement membrane showed irregular wrinkling and branching. The proximal tubular cells showed damage such as dilation of endoplasmic reticulum, accumulation of glycogen granules, and pyknotic nucleus. The changes also included swelling of the mitochondria and reduction of the cristae up to total destruction. The distal tubular changes included electron lucency and vacuolation of cytoplasm. The distal convoluted tubule wall showed edematous epithelial cells, formation of blebs, and microvilli loss. These results suggest that subchronic exposure of rats to Ekalux causes ultrastructural changes in renal corpuscle and marked ultrastructural changes in proximal and distal tubules.

Rhabdomyolysis with acute tubular necrosis following occupational inhalation of thinners.

PubMed

Ngajilo, D; Ehrlich, R

2017-07-01

Thinners are mixtures of organic solvents commonly containing toluene, xylene, acetone, hexane, benzene and methyl isobutyl ketone. This report describes a case of rhabdomyolysis with acute tubular necrosis and renal failure, most likely attributable to toluene, following occupational exposure to thinners while cleaning a steel water tank. These adverse health effects have previously been reported following acute poisoning or intentional inhalation by drug abusers, but rarely in the occupational setting. Poor working conditions, lack of health and safety training and delayed treatment contributed to the onset and severity of the patient's complications. This case emphasizes the need for strict control measures, including adequate ventilation, training on working in confined spaces, appropriate personal protective equipment and emergency rescue procedures in such settings. In addition, rhabdomyolysis, acute tubular necrosis and renal failure should be added to safety data material as possible complications of excessive inhalation of thinners. © The Author 2017. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury

PubMed Central

Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan; Geurts, Aron M; Usa, Kristie; Jacob, Howard J; Cowley, Allen W; Wang, Niansong; Liang, Mingyu

2015-01-01

Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury. PMID:26108065

Renal and Glycemic Effects of High-Dose Chromium Picolinate in db/db Mice: Assessment of DNA Damage

PubMed Central

Mozaffari, Mahmood S.; Baban, Babak; Abdelsayed, Rafik; Liu, Jun Yao; Wimborne, Hereward; Rodriguez, Nancy; Abebe, Worku

2011-01-01

This study examined renal and glycemic effects of chromium picolinate (Cr(pic)3) supplementation in the context of its purported potential for DNA damage. In preventional protocol, male obese diabetic db/db mice were fed diets either lacking or containing 5, 10 or 100 mg/kg chromium as Cr(pic)3 from 6 to 24 weeks of age; male lean nondiabetic db/m mice served as controls. Untreated db/db mice displayed increased plasma glucose and insulin, hemoglobin A1c, renal tissue advanced glycation end (AGE) products, albuminuria, glomerular mesangial expansion, urinary 8-hydroxydeoxyguanosine (8-OHdG, an index of oxidative DNA damage) and renal tissue immunostaining for γH2AX (a marker of double-strand DNA breaks) compared to db/m controls. Creatinine clearance was lower while blood pressure was similar between untreated db/db mice and their db/m controls. High Cr(pic)3 intake (i.e., 100 mg/kg diet) mildly improved glycemic status and albuminuria without affecting blood pressure or creatinine clearance. Treatment with Cr(pic)3 did not increase DNA damage despite marked renal accumulation of chromium. In interventional protocol, effects of diets containing 0, 100 and 250 mg/kg supplemental chromium, from 12 to 24 weeks of age, were examined in db/db mice. The results generally revealed similar effects to those of the 100 mg/kg diet of the preventional protocol. In conclusion, the severely hyperglycemic db/db mouse displays renal structural and functional abnormalities in association with DNA damage. High-dose Cr(pic)3 treatment mildly improves glycemic control and it causes moderate reduction in albuminuria, without affecting histopathological appearance of the kidney and increasing the risk for DNA damage. PMID:21959055

Renal and glycemic effects of high-dose chromium picolinate in db/db mice: assessment of DNA damage.

PubMed

Mozaffari, Mahmood S; Baban, Babak; Abdelsayed, Rafik; Liu, Jun Yao; Wimborne, Hereward; Rodriguez, Nancy; Abebe, Worku

2012-08-01

This study examined renal and glycemic effects of chromium picolinate [Cr(pic)3] supplementation in the context of its purported potential for DNA damage. In preventional protocol, male obese diabetic db/db mice were fed diets either lacking or containing 5, 10 or 100 mg/kg chromium as Cr(pic)3 from 6 to 24 weeks of age; male lean nondiabetic db/m mice served as controls. Untreated db/db mice displayed increased plasma glucose and insulin, hemoglobin A1c, renal tissue advanced glycation end products, albuminuria, glomerular mesangial expansion, urinary 8-hydroxydeoxyguanosine (an index of oxidative DNA damage) and renal tissue immunostaining for γH2AX (a marker of double-strand DNA breaks) compared to db/m controls. Creatinine clearance was lower in untreated db/db mice than their db/m controls, while blood pressure was similar. High Cr(pic)3 intake (i.e., 100-mg/kg diet) mildly improved glycemic status and albuminuria without affecting blood pressure or creatinine clearance. Treatment with Cr(pic)3 did not increase DNA damage despite marked renal accumulation of chromium. In interventional protocol, effects of diets containing 0, 100 and 250 mg/kg supplemental chromium, from 12 to 24 weeks of age, were examined in db/db mice. The results generally revealed similar effects to those of the 100-mg/kg diet of the preventional protocol. In conclusion, the severely hyperglycemic db/db mouse displays renal structural and functional abnormalities in association with DNA damage. High-dose Cr(pic)3 treatment mildly improves glycemic control, and it causes moderate reduction in albuminuria, without affecting the histopathological appearance of the kidney and increasing the risk for DNA damage. Copyright © 2012 Elsevier Inc. All rights reserved.

Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation

PubMed Central

Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

2016-01-01

Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment. PMID:27999546

Effects of Escherichia coli subtilase cytotoxin and Shiga toxin 2 on primary cultures of human renal tubular epithelial cells.

PubMed

Márquez, Laura B; Velázquez, Natalia; Repetto, Horacio A; Paton, Adrienne W; Paton, James C; Ibarra, Cristina; Silberstein, Claudia

2014-01-01

Shiga toxin (Stx)-producing Escherichia coli (STEC) cause post-diarrhea Hemolytic Uremic Syndrome (HUS), which is the most common cause of acute renal failure in children in many parts of the world. Several non-O157 STEC strains also produce Subtilase cytotoxin (SubAB) that may contribute to HUS pathogenesis. The aim of the present work was to examine the cytotoxic effects of SubAB on primary cultures of human cortical renal tubular epithelial cells (HRTEC) and compare its effects with those produced by Shiga toxin type 2 (Stx2), in order to evaluate their contribution to renal injury in HUS. For this purpose, cell viability, proliferation rate, and apoptosis were assayed on HRTEC incubated with SubAB and/or Stx2 toxins. SubAB significantly reduced cell viability and cell proliferation rate, as well as stimulating cell apoptosis in HRTEC cultures in a time dependent manner. However, HRTEC cultures were significantly more sensitive to the cytotoxic effects of Stx2 than those produced by SubAB. No synergism was observed when HRTEC were co-incubated with both SubAB and Stx2. When HRTEC were incubated with the inactive SubAA272B toxin, results were similar to those in untreated control cells. Similar stimulation of apoptosis was observed in Vero cells incubated with SubAB or/and Stx2, compared to HRTEC. In conclusion, primary cultures of HRTEC are significantly sensitive to the cytotoxic effects of SubAB, although, in a lesser extent compared to Stx2.

Urinary protein excretion profile: A contribution for subclinical renal damage identification among environmental heavy metals exposure in Southeast Brazil

NASA Astrophysics Data System (ADS)

Garlipp, C. R.; Bottini, P. V.; de Capitan, E. M.; Pinho, M. C.; Panzan, A. D. N.; Sakuma, A. M. A.; Paoliello, M. B.

2003-05-01

In Southeast Brazil. Ribeira Valley region has been a major public health concern due to he environmental heavy metals contamination indexes of vegetation, rocks and aquifers, caused by locai mining in the past. Human contamination low levels of heavy rnetals doesn't cause acute intoxication but ni chronic exposure, renal damage may occur with progressive tubuJointerstitial changes evolvil1g to glomemlar 1esiol1, ln this stndy we invesligated the relationship between thc profile of utillan, excreted proteins (glomerular or lubular origin) of arsenic and mercury and blood lead concentration in chiJdren and adults from highly e) qJosed regions of the Ribeira Valley. The subjects were classieed as GROUP 1 (GI; higher environmental risk n=333) and GROUP 2 (G2; lower risk of contamination. n=104). In order to determine the urinary excretion of total protein, albumin (MA, glomerular marker) and alpha i microglobulin (AIM, tubular marker) and the blood lead concentrations. random wine and blood samples were obtaiiied. Plasmatic lead levels were assessed by atomic absorption spectrometty with graphite fumace. Totai protein concentration (PROT) was assessed on a biochemical analyzer ,progallol red method). MA and AIM were determined by nephelometric method. Croup 1 showcd a higher frequency of altered urinary excretion of PROT (GI=3.4%; G2=1.0%), MA (Gl=9.0%; G2=5.1%) and AIM (Gt=7.5%, G2=3.8%), without significant differences between both groups. Elevated arscnic levels were more prevaient among subjects from Group 1 (2.8.8%) and demonstrated a significant corrolation with abiiormal iirinarv excretion of ilbumin and alpha-l-micrglobulin (p=0.019).Leadaand mercury levels showed no difference among the groups and no correlation will MAa and/or M. Oti-c dala suggests that abnormal itrinary protein excretion is relatively frequent in this population independently of the plasmatic or urinaryl heavy metal levels. The early detection of possible renal damage become necessary for

Cleistanthus collinus induces type I distal renal tubular acidosis and type II respiratory failure in rats.

PubMed

Maneksh, Delinda; Sidharthan, Anita; Kettimuthu, Kavithapriya; Kanthakumar, Praghalathan; Lourthuraj, Amala A; Ramachandran, Anup; Subramani, Sathya

2010-06-01

A water decoction of the poisonous shrub Cleistanthus collinus is used for suicidal purposes. The mortality rate is 28%. The clinical profile includes distal renal tubular acidosis (DRTA) and respiratory failure. The mechanism of toxicity is unclear. To demonstrate features of C. collinus toxicity in a rat model and to identify its mechanism(s) of action. Rats were anesthetized and the carotid artery was cannulated. Electrocardiogram and respiratory movements were recorded. Either aqueous extract of C. collinus or control solution was administered intraperitoneally. Serial measurements of blood gases, electrolytes and urinary pH were made. Isolated brush border and basolateral membranes from rat kidney were incubated with C. collinus extract and reduction in ATPase activity was assessed. Venous blood samples from human volunteers and rats were incubated with an acetone extract of C. collinus and plasma potassium was estimated as an assay for sodium-potassium pump activity. The mortality was 100% in tests and 17% in controls. Terminal event in test animals was respiratory arrest. Controls had metabolic acidosis, respiratory compensation acidic urine and hyperkalemia. Test animals showed respiratory acidosis, alkaline urine and low blood potassium as compared to controls. C. collinus extract inhibited ATPase activity in rat kidney. Plasma K(+) did not increase in human blood incubated with C. collinus extract. Active principles of C. collinus inhibit proton pumps in the renal brush border, resulting in type I DRTA in rats. There is no inhibition of sodium-potassium pump activity. Test animals develop respiratory acidosis, and the immediate cause of death is respiratory arrest.

Staphylococcus aureus Sepsis Induces Early Renal Mitochondrial DNA Repair and Mitochondrial Biogenesis in Mice

PubMed Central

Bartz, Raquel R.; Fu, Ping; Suliman, Hagir B.; Crowley, Stephen D.; MacGarvey, Nancy Chou; Welty-Wolf, Karen; Piantadosi, Claude A.

2014-01-01

Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection. PMID:24988481

Therapeutical relevance of MAP-kinase inhibitors in renal diseases: current knowledge and future clinical perspectives.

PubMed

Grande, M Teresa; López-Novoa, José M

2008-01-01

Renal failure, both acute and chronic, represents an important health problem by its social, sanitary and economic aspects. Mitogen-activated protein kinases (MAPK) are a family of mediators involved in the transduction of extracellular stimuli to intracellular responses. The best studied members of this family are extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), Jun NH(2)-terminal kinase (JNK), p38 kinase and extracellular signal regulated kinases 5 (ERK5) also known as big MAP Kinase 1 (BMK1). MAPKs plays a role in regulating renal function and all these pathways have been demonstrated to be activated in many "in vivo" and cellular models or renal failure. As MAP kinases are key regulators in the control of cell proliferation and cell death, many more or less specific inhibitors of these pathways are being developed for the treatment of tumors. The purpose of this review is to examine the data available on the role of MAPKs activation in "in vivo" models of renal failure, as well as in different renal cell types (especially in mesangial cells, podocytes, tubular epithelial cells and fibroblasts) subjected to stress or damage. We have also reviewed the effect of MAPKs inhibition on renal damage, both "in vivo" and "in vitro". Data collected allow to suggest that therapy of chronic and acute renal disease with MAPKs inhibitors is a promising therapeutic area, although much more basic and clinical studies are necessary before this kind of therapy can be used in the everyday clinic.

Albumin-induced apoptosis of tubular cells is modulated by BASP1

PubMed Central

Sanchez-Niño, M D; Fernandez-Fernandez, B; Perez-Gomez, M V; Poveda, J; Sanz, A B; Cannata-Ortiz, P; Ruiz-Ortega, M; Egido, J; Selgas, R; Ortiz, A

2015-01-01

Albuminuria promotes tubular injury and cell death, and is associated with faster progression of chronic kidney disease (CKD) to end-stage renal disease. However, the molecular mechanisms regulating tubular cell death in response to albuminuria are not fully understood. Brain abundant signal protein 1 (BASP1) was recently shown to mediate glucose-induced apoptosis in tubular cells. We have studied the role of BASP1 in albumin-induced tubular cell death. BASP1 expression was studied in experimental puromycin aminonucleoside-induced nephrotic syndrome in rats and in human nephrotic syndrome. The role of BASP1 in albumin-induced apoptosis was studied in cultured human HK2 proximal tubular epithelial cells. Puromycin aminonucleoside induced proteinuria and increased total kidney BASP1 mRNA and protein expression. Immunohistochemistry localized the increased BASP1 to tubular cells. BASP1 expression colocalized with deoxynucleotidyl-transferase-mediated dUTP nick-end labeling staining for apoptotic cells. Increased tubular BASP1 expression was observed in human proteinuric nephropathy by immunohistochemistry, providing evidence for potential clinical relevance. In cultured tubular cells, albumin induced apoptosis and increased BASP1 mRNA and protein expression at 6–48 h. Confocal microscopy localized the increased BASP1 expression in albumin-treated cells mainly to the perinuclear area. A peripheral location near the cell membrane was more conspicuous in albumin-treated apoptotic cells, where it colocalized with actin. Inhibition of BASP1 expression by a BASP1 siRNA protected from albumin-induced apoptosis. In conclusion, albumin-induced apoptosis in tubular cells is BASP1-dependent. This information may be used to design novel therapeutic approaches to slow CKD progression based on protection of tubular cells from the adverse consequences of albuminuria. PMID:25675304

Clinical types and drug therapy of renal impairment in cirrhosis

PubMed Central

Rodés, J.; Bosch, J.; Arroyo, V.

1975-01-01

Four separate types of renal failure in cirrhosis are described: functional renal failure; diuretic induced uraemia; acute tubular necrosis; chronic intrinsic renal disease. Functional renal failure may arise spontaneously or be precipitated by such factors as haemorrhage, surgery, or infection. It carries a poor prognosis but preliminary results of treating this condition with plasma volume expansion in combination with high doses of furosemide are encouraging. PMID:1234328

Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus

PubMed Central

Suzuki, Takafumi; Seki, Shiori; Hiramoto, Keiichiro; Naganuma, Eriko; Kobayashi, Eri H.; Yamaoka, Ayaka; Baird, Liam; Takahashi, Nobuyuki; Sato, Hiroshi; Yamamoto, Masayuki

2017-01-01

NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2. PMID:28233855

Mitochondrial Modulation by Epigallocatechin 3-Gallate Ameliorates Cisplatin Induced Renal Injury through Decreasing Oxidative/Nitrative Stress, Inflammation and NF-kB in Mice

PubMed Central

Wang, Xueping; Wang, Ping; Fu, Guanghou; Meng, Hongzhou; Wang, Yimin; Jin, Baiye

2015-01-01

Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for

Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells.

PubMed

Liu, Jing; Livingston, Man J; Dong, Guie; Tang, Chengyuan; Su, Yunchao; Wu, Guangyu; Yin, Xiao-Ming; Dong, Zheng

2018-02-23

Histone deacetylase inhibitors (HDACi) have therapeutic effects in models of various renal diseases including acute kidney injury (AKI); however, the underlying mechanism remains unclear. Here we demonstrate that two widely tested HDACi (suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA)) protect the kidneys in cisplatin-induced AKI by enhancing autophagy. In cultured renal proximal tubular cells, SAHA and TSA enhanced autophagy during cisplatin treatment. We further verified the protective effect of TSA against cisplatin-induced apoptosis in these cells. Notably, inhibition of autophagy by chloroquine or by autophagy gene 7 (Atg7) ablation diminished the protective effect of TSA. In mice, TSA increased autophagy in renal proximal tubules and protected against cisplatin-induced AKI. The in vivo effect of TSA was also abolished by chloroquine and by Atg7 knockout specifically from renal proximal tubules. Mechanistically, TSA stimulated AMPK and inactivated mTOR during cisplatin treatment of proximal tubule cells and kidneys in mice. Together, these results suggest that HDACi may protect kidneys by activating autophagy in proximal tubular cells.

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits.

PubMed

Ding, Wen; Yousefi, Keyvan; Goncalves, Stefania; Goldstein, Bradley J; Sabater, Alfonso L; Kloosterboer, Amy; Ritter, Portia; Lambert, Guerline; Mendez, Armando J; Shehadeh, Lina A

2018-03-22

Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr-/- mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration.

[Peritubular capillary injury in Chinese herb guan-mu-tong-induced acute tubular necrosis].

PubMed

Yang, Li; Li, Xiao-mei; Wang, Su-xia; Wang, Hai-yan

2005-07-01

To explore the role and mechanisms of peritubular capillary (PTC) injury in the progression of Chinese Herb guan-mu-tong (GMT, aristolochiae manshuriensis kom) induced acute tubular necrosis (GMT-ATN). Renal biopsy tissue from 4 cases of GMT-ATN and 5 cases of antibiotic induced ATN (A-ATN) were included in the study. Tubulointerstitial injury was semi-quantitatively assessed. Immunohistochemical SP method was applied to reveal PTC as well as the expression of vascular endothelial growth factor (VEGF). Ultra microstructure of endothelial cells and basement membrane of PTC was detected by electronic microscopy (EM). 5 cases of minor mesangioproliferative non-IgA glomerulonephritis were selected as a control group. The density of PTC was decreased significantly in GMT-ATN, as compared with the A-ATN and control group (211.08 +/- 56.15 vs 413.54 +/- 66.59, 536.62 +/- 68.38, P < 0.01). Dilated and deformed PTC lumina were noted in GMT-ATN with some endothelial cells and basement membrane partially disrupted. Most endothelial cells were found to be swollen with vacuoles dispersed in the cell plasma. The basement membrane was partially shrunk and thickened. The expression of VEGF in renal tubular epithelial cells (RTEC) was much less in the GMT-ATN than that in A-ATN group 2.1 (0-3.86)% vs [42.5 (31.33-60.25)%, P < 0.01], even though it was higher than that in the control group [23.1 (18.2-39.5)%, P < 0.01]; the expression was correlated with PTC density. Close correlation was also found between RTEC regeneration and PTC density, as well as VEGF expression (r = 0.880 and 0.802 respectively, P < 0.01). PTC was markedly injured in GMT-ATN; this could be one of the cause for the continuously progressing tubulointerstitial damage. The low expression of VEGF in RTEC might contribute to the PTC injury process.

Depletion of Gut Microbiota Protects against Renal Ischemia-Reperfusion Injury

PubMed Central

Rampanelli, Elena; Stroo, Ingrid; Butter, Loes M.; Teske, Gwendoline J.; Claessen, Nike; Stokman, Geurt; Florquin, Sandrine; Leemans, Jaklien C.; Dessing, Mark C.

2017-01-01

An accumulating body of evidence shows that gut microbiota fulfill an important role in health and disease by modulating local and systemic immunity. The importance of the microbiome in the development of kidney disease, however, is largely unknown. To study this concept, we depleted gut microbiota with broad-spectrum antibiotics and performed renal ischemia-reperfusion (I/R) injury in mice. Depletion of the microbiota significantly attenuated renal damage, dysfunction, and remote organ injury and maintained tubular integrity after renal I/R injury. Gut flora–depleted mice expressed lower levels of F4/80 and chemokine receptors CX3CR1 and CCR2 in the F4/80+ renal resident macrophage population and bone marrow (BM) monocytes than did control mice. Additionally, compared with control BM monocytes, BM monocytes from gut flora–depleted mice had decreased migratory capacity toward CX3CL1 and CCL2 ligands. To study whether these effects were driven by depletion of the microbiota, we performed fecal transplants in antibiotic-treated mice and found that transplant of fecal material from an untreated mouse abolished the protective effect of microbiota depletion upon renal I/R injury. In conclusion, we show that depletion of gut microbiota profoundly protects against renal I/R injury by reducing maturation status of F4/80+ renal resident macrophages and BM monocytes. Therefore, dampening the inflammatory response by targeting microbiota-derived mediators might be a promising therapy against I/R injury. PMID:27927779

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

PubMed Central

Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

2015-01-01

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

Renal Tubule Repair: Is Wnt/β-Catenin a Friend or Foe?

PubMed

Gewin, Leslie S

2018-01-24

Wnt/β-catenin signaling is extremely important for proper kidney development. This pathway is also upregulated in injured renal tubular epithelia, both in acute kidney injury and chronic kidney disease. The renal tubular epithelium is an important target of kidney injury, and its response (repair versus persistent injury) is critical for determining whether tubulointerstitial fibrosis, the hallmark of chronic kidney disease, develops. This review discusses how Wnt/β-catenin signaling in the injured tubular epithelia promotes either repair or fibrosis after kidney injury. There is data suggesting that epithelial Wnt/β-catenin signaling is beneficial in acute kidney injury and important in tubular progenitors responsible for epithelial repair. The role of Wnt/β-catenin signaling in chronically injured epithelia is less clear. There is convincing data that Wnt/β-catenin signaling in interstitial fibroblasts and pericytes contributes to the extracellular matrix accumulation that defines fibrosis. However, some recent studies question whether Wnt/β-catenin signaling in chronically injured epithelia actually promotes fibrosis or repair.

Hemodynamic and renal implications of sodium-glucose cotransporter- 2 inhibitors in type 2 diabetes mellitus.

PubMed

Tejedor Jorge, Alberto

2016-11-01

In DM2, there is increased expression of the proximal glucose transporter SGLT2. The increased glucose reabsorption from the urine to the proximal tubule and subsequently to the bloodstream, has three direct effects on the prognosis of patients with DM2: a) it increases the daily glucose load by raising the renal threshold for glucose, thus augmenting requirements for oral antidiabetics and insulin. This progressive increase occurs throughout the course of the disease and in parallel with the increase in renal mass (renal hypertrophy); b) because of the greater glucose reabsorption, glycosuria is lower than the level corresponding to glycaemia, decreasing the stimulus on the tubuloglomerular feedback system of the distal nephron. As a result, the glomerular vasodilation caused by hyperglycaemia is not arrested, maintaining glomerular hyperfiltration, and c) the excess glucose transported to the proximal tubular cells modifies their redox status, increasing local production of glycosylating products and activating local production of proinflammatory and profibrotic proliferative mediators. These mediators are responsible for the direct free radical damage to proximal tubular cells, for increased SGLT2 expression, increased production of collagen IV and extracellular matrix, and activation of monocyte/macrophages able to cause endothelial injury. The use of SGLT2 inhibitors not only reduces the reabsorption of glucose from the glomerular filtrate back into the circulationthus improving metabolic control in diabetesbut also restores tubuloglomerular feedback by increasing glycosuria and distal urinary flow. However, the most notable effect is due to inhibition of glucose entry to the proximal tubular cells. Glycosuria is toxic to the kidney: it harms glucosetransporting cells, that is, the proximal cells, which contain SGLT2. In animal models, SGLT2 inhibition reduces local production of oxygen-free radicals, the formation of mesangial matrix and collagen IV

Early onset acute tubular necrosis following single infusion of zoledronate.

PubMed

Yachoui, Ralph

2016-01-01

Zoledronate is a highly potent bisphosphonate widely used in the treatment of postmenopausal osteoporosis. We report the first occurrence of toxic acute tubular necrosis (ATN) following treatment with zoledronate in a patient with osteoporosis. A 63-year-old Caucasian female with rheumatoid arthritis on anti-immune agents received a single dose of zoledronic acid (reclast) for worsening osteoporosis. Twelve days later, she developed renal failure with a rise in serum creatinine from a baseline level of 1.1 mg/dL to 5.5 mg/dL. Renal biopsy showed toxic ATN. Zoledronate was discontinued and the patient had subsequent gradual improvement in renal function with final serum creatinine of 1.8 mg/dL at 1 month of follow up. Careful monitoring of serum creatinine and awareness of the potential nephrotoxicity may avert the development of acute renal failure in osteoporosis patients treated with this agent.

Early onset acute tubular necrosis following single infusion of zoledronate

PubMed Central

Yachoui, Ralph

2016-01-01

Summary Zoledronate is a highly potent bisphosphonate widely used in the treatment of postmenopausal osteoporosis. We report the first occurrence of toxic acute tubular necrosis (ATN) following treatment with zoledronate in a patient with osteoporosis. A 63-year-old Caucasian female with rheumatoid arthritis on anti-immune agents received a single dose of zoledronic acid (reclast) for worsening osteoporosis. Twelve days later, she developed renal failure with a rise in serum creatinine from a baseline level of 1.1 mg/dL to 5.5 mg/dL. Renal biopsy showed toxic ATN. Zoledronate was discontinued and the patient had subsequent gradual improvement in renal function with final serum creatinine of 1.8 mg/dL at 1 month of follow up. Careful monitoring of serum creatinine and awareness of the potential nephrotoxicity may avert the development of acute renal failure in osteoporosis patients treated with this agent. PMID:27920815

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.

PubMed

Rong, Song; Hueper, Katja; Kirsch, Torsten; Greite, Robert; Klemann, Christian; Mengel, Michael; Meier, Matthias; Menne, Jan; Leitges, Michael; Susnik, Nathan; Meier, Martin; Haller, Hermann; Shushakova, Nelli; Gueler, Faikah

2014-09-15

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H(2b) PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H(2d) recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI. Copyright © 2014 the American Physiological Society.

Nephro-protective effect of a novel formulation of unopened coconut inflorescence sap powder on gentamicin induced renal damage by modulating oxidative stress and inflammatory markers.

PubMed

Jose, Svenia P; S, Asha; Im, Krishnakumar; M, Ratheesh; Santhosh, Savitha; S, Sandya; B, Girish Kumar; C, Pramod

2017-01-01

Fresh oyster white translucent sap obtained from the tender unopened inflorescence of coconut trees (Cocos nucifera) is identified to have great health benefits. Drug induced Nephrotoxicity is one of the major causes of renal damage in present generation. As a therapeutic agent, gentamicin imparts direct toxicity to kidney, resulting in acute tubular necrosis, glomerular and tubulointerstitial injury, haemodynamically mediated damage and obstructive nephropathy.There exists an increasing demand for safe and natural agents for the treatment and/or preventionofchronic nephrotoxicity and pathogenesis of kidney diseases. Our study shows the nephro protective/curing effect of a novel powder formulation of micronutrient enriched, unfermented coconut flower sap (CSP). The study was performed on adult male Wistar rats. The animals were grouped into three and treated separately with vehicle, gentamicin and gentamicin+CSP for 16days. Initially, gentamicin treatment significantly (p<0.05)reduced thelevels of antioxidant enzymes (SOD, CAT, GPx) and GSH and increased (p<0.05) the levels of creatinine, uric acid, urea, inflammatory markers (nitrite, IL-6, TNF- α, iNOS) and lipid peroxidation. Supplementation of coconut flower sap powder showed significant (p<0.05) reversal of all these biochemical parameters indicating an effective inhibition of the pathogenesis of nephrotoxicity and kidney disease. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

PubMed

Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

2017-09-01

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury

PubMed Central

Thomasova, Dana; Ebrahim, Martrez; Fleckinger, Kristina; Li, Moying; Molnar, Jakob; Popper, Bastian; Liapis, Helen; Kotb, Ahmed M; Siegerist, Florian; Endlich, Nicole; Anders, Hans-Joachim

2016-01-01

Murine double minute-2 (MDM2) is an E3-ubiquitin ligase and the main negative regulator of tumor suppressor gene p53. MDM2 has also a non-redundant function as a modulator of NF-kB signaling. As such it promotes proliferation and inflammation. MDM2 is highly expressed in the unchallenged tubular epithelial cells and we hypothesized that MDM2 is necessary for their survival and homeostasis. MDM2 knockdown by siRNA or by genetic depletion resulted in demise of tubular cells in vitro. This phenotype was completely rescued by concomitant knockdown of p53, thus suggesting p53 dependency. In vivo experiments in the zebrafish model demonstrated that the tubulus cells of the larvae undergo cell death after the knockdown of mdm2. Doxycycline-induced deletion of MDM2 in tubular cell-specific MDM2-knockout mice Pax8rtTa-cre; MDM2f/f caused acute kidney injury with increased plasma creatinine and blood urea nitrogen and sharp decline of glomerular filtration rate. Histological analysis showed massive swelling of renal tubular cells and later their loss and extensive tubular dilation, markedly in proximal tubules. Ultrastructural changes of tubular epithelial cells included swelling of the cytoplasm and mitochondria with the loss of cristae and their transformation in the vacuoles. The pathological phenotype of the tubular cell-specific MDM2-knockout mouse model was completely rescued by co-deletion of p53. Tubular epithelium compensates only partially for the cell loss caused by MDM2 depletion by proliferation of surviving tubular cells, with incomplete MDM2 deletion, but rather mesenchymal healing occurs. We conclude that MDM2 is a non-redundant survival factor for proximal tubular cells by protecting them from spontaneous p53 overexpression-related cell death. PMID:27882940

Micropuncture studies of the recovery phase of myohemoglobinuric acute renal failure in the rat

PubMed Central

Oken, Donald E.; DiBona, Gerald F.; McDonald, Franklin D.

1970-01-01

Micropuncture studies of the recovery phase of glycerol-induced myohemoglobinuric acute renal failure were performed in rats whose blood urea nitrogen (BUN) had fallen at least 20% below its peak value. The glomerular filtration rate (GFR) of individual nephrons in a single kidney in the recovery period generally either was in the normal range or minimal. Each animal's BUN concentration at the time of the study was inversely related to the proportion of functioning surface nephrons, but did not correlate with individual nephron GFR values. Proximal tubule fractional water absorption was significantly depressed as manifested by both depressed inulin (TF/P) values and supernormal volumes of collections, a finding which, in the absence of a urea-induced osmotic diuresis, suggests impaired sodium transport by the damaged nephron. The mean proximal tubule hydrostatic pressure in recovery was normal and there was little variation in pressure among functioning nephrons. It is concluded that recovery from this model of acute renal failure reflects the progressive recruitment of increasing numbers of functioning nephrons. The recovery of individual nephron glomerular filtration, once begun, was rapid and complete. No evidence could be adduced that the gradual return of renal function towards normal reflects a slow release of tubular obstruction or repair of disrupted tubular epithelium. Rather, recovery appeared to be directly attributable to the return of an adequate effective glomerular filtration pressure. Significant limitation in proximal tubule water absorption persisted after individual nephron GFR had returned to normal or supernormal values in this model of experimental acute renal failure in the rat, a finding which readily accounts for the diuresis associated with the recovery phase of this syndrome. PMID:5443173

Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response.

PubMed