Experimental nephrology最新文献

{"title":"Role of intrarenal endothelin 1, endothelin 3, and angiotensin II expression in chronic cyclosporin A nephrotoxicity in rats.","authors":"C Ramírez,&nbsp;A Olmo,&nbsp;F O'Valle,&nbsp;M Masseroli,&nbsp;M Aguilar,&nbsp;M Gómez-Morales,&nbsp;F Revelles,&nbsp;M J García-Chicano,&nbsp;F Arrebola,&nbsp;M E Reguero,&nbsp;R G del Moral","doi":"10.1159/000020664","DOIUrl":"https://doi.org/10.1159/000020664","url":null,"abstract":"<p><p>Endothelin 1 (Et1) is widely expressed in the kidney and is related to several functions and to pathological conditions with progression towards sclerosis. The function of endothelin 3 (Et3) at the renal level is debatable, but it could have an important regulatory function in the reabsorption of water through its action on tubular type B receptors. Angiotensin II has recently been implicated as the principal factor responsible for the progression of interstitial fibrosis induced by cyclosporin A (CsA). We investigated this relationship in vivo and analyzed the modifications induced by CsA toxicity in Sprague-Dawley rats treated with 25 mg/kg/day of CsA for 28 and 56 days. Immunohistochemical methods and molecular analysis were used to study the expression of Et1 and Et3 and immunohistochemistry alone to determine the intrarenal expression of angiotensin II. Rats treated with CsA developed chronic nephrotoxicity lesions; semiquantitative analyses of hyaline arteriolopathy revealed that the passage of time affected the extent of this lesion and led to the diminution of the total glomerular area. Immunohistochemical results showed that chronic CsA treatment induced moderate secretion of Et1 and Et3 at tubular and glomerular levels and that the local expression of angiotensin II in the treatment groups was more evident than in control animals. Besides, the mRNA levels of preproEt3 showed a dramatic increase from 28 days after CsA treatment (control group 0.07+/-0.11 vs. CsA group 0.48+/-0.11, p<0.01), while the mRNA levels of preproEt1 increased from 56 days (control group 0.15+/-0.05 vs. CsA group 0.34+/-0.09, p< 0.05). At 28 days, renal lesions correlated strongly with the mRNA levels of Et3 (r>0.50, p<0.01). However, at 56 days, the key finding was the strong correlation of the most important analytical, histological, and immunohistochemical parameters of CsA nephrotoxicity with Et1 mRNA levels (r>0.50, p<0.01). These results support the hypothesis that the clinical and morphological phenomena linked with CsA nephrotoxicity are related to hypersecretion of endothelins and local expression of angiotensin II in the outer medulla and medullary rays; Et3 and angiotensin II are the first to act, followed subsequently by Et1.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 3","pages":"161-72"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21656743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cloning of rabbit Cct6 and the distribution of the Cct complex in mammalian tissues.","authors":"G J Schwartz,&nbsp;A M Kittelberger,&nbsp;G B Segel","doi":"10.1159/000020663","DOIUrl":"https://doi.org/10.1159/000020663","url":null,"abstract":"<p><p>Cct6 protein is one of the subunits of the Cct complex involved in ATP-dependent folding of cellular proteins. We used the cDNA of the human CCT6 subunit to obtain a full-length cDNA from a rabbit kidney cortex library. Two transcripts of 2 and 2.5 kb were detected in rabbit kidney and liver by Northern analysis. The rabbit CCT6 was 93% identical to the human gene; the deduced amino acid sequence was 97% identical. A phylogenetic analysis of Cct6 proteins from mouse, rabbit, human, and yeast showed greater similarities of Cct6 protein among the species than among other Cct subunits. The ATP-binding sites were perfectly conserved among mammals and yeast, supporting the role of Cct complex in ATP-dependent protein folding. Using a polyclonal antibody to human Cct6 protein and Western analysis, we found expression of this subunit in a variety of rabbit organs and tissues, as well as in bovine testes, human lymphocytes, human and rabbit reticulocytes, and in two cultured kidney cell lines. We also found Cct1 protein by Western analysis in several rabbit organs as well as in bovine testes. These data characterize the rabbit Cct6 subunit and compare it to its homologues. The Western analyses support the concept that Cct complex is widely distributed among tissues and highly conserved among eukaryotes.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 3","pages":"152-60"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21656865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular basis of cystinuria: an update.","authors":"P Goodyer,&nbsp;M Boutros,&nbsp;R Rozen","doi":"10.1159/000020659","DOIUrl":"https://doi.org/10.1159/000020659","url":null,"abstract":"<p><p>Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal proximal tubule and small intestine. In 1992, a cDNA (rBAT) was isolated from kidney which induced high-affinity, sodium-independent uptake of cystine and dibasic amino acids when expressed in Xenopus oocytes. The rBAT gene was mapped to a region of chromosome 2p known to contain a cystinuria locus, and rBAT expression was demonstrated in the straight (S3) portion of renal proximal tubule and small intestine. Over 30 distinct rBAT mutations have been described in patients who inherit two fully recessive (type I) cystinuria genes. Recently, the second cystinuria gene (SLC7A9) on chromosome 19q was identified; SLC7A9 mutations were shown to cause the incompletely recessive form of cystinuria (types II and III). Patients who inherit two mutant SLC7A9 genes have recurrent nephrolithiasis comparable to those with two rBAT mutations. In some cystinuria families, patients inherit a fully recessive allele from one parent and an incompletely recessive allele from the other parent; patients with this 'mixed type' of cystinuria have somewhat milder disease. It is not yet clear whether this form of cystinuria involves rBAT as well as SLC7A9 mutations. Current evidence suggests that the transmembrane channel mediating uptake of cystine and dibasic amino acids at the luminal surface is encoded by SLC7A9; the smaller rBAT protein forms a heterodimeric complex with this channel and is critical for its targetting to the luminal membrane.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 3","pages":"123-7"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020659","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21656861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arginase in glomerulonephritis.","authors":"S N Waddington,&nbsp;V Cattell","doi":"10.1159/000020660","DOIUrl":"https://doi.org/10.1159/000020660","url":null,"abstract":"<p><p>Arginase metabolizes L-arginine to L-ornithine and urea. Two arginase isoforms, AI (liver arginase) and AII (ubiquitously expressed, functions unknown), have been identified. It is clear that arginases potentially have important roles in addition to urea generation for high concentrations are present at inflammatory sites. Regulation occurs through cytokines, substrate competition and products of nitric oxide (NO) metabolism. The functions of arginases at inflammatory sites are unknown, but may include regulation of apoptosis and NO production and generation of structural and cellular protein precursors. In glomerulonephritis there is increased arginase activity in nephritic glomeruli following a pattern similar to that in wound healing. The level can be further increased by NO inhibition suggesting substrate competition. The potential sources in the inflamed glomerulus include infiltrating leucocytes and mesangial cells, and the predominant isoform expressed is AI (AII predominates under physiological conditions). The recent identification of different isoforms of arginase has been an important step towards understanding the significance of arginase activity in glomerulonephritis.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 3","pages":"128-34"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21656862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition with antisense oligonucleotide suggests that IkappaB-alpha does not form a negative autoregulatory loop for NF-kappaB in mesangial cells.","authors":"R B Auwardt,&nbsp;S J Mudge,&nbsp;C Chen,&nbsp;D A Power","doi":"10.1159/000020662","DOIUrl":"https://doi.org/10.1159/000020662","url":null,"abstract":"<p><p>The IkappaB proteins are important in the regulation of the NF-kappaB/Rel group of transcription factors which are pivotal in the inflammatory response. IkappaB-alpha is itself upregulated by activation of NF-kappaB and is postulated to be part of a negative feedback loop. This role of IkappaB-alpha has been challenged, however, by recent evidence that demonstrates (1) continued activation of NF-kappaB in mesangial and endothelial cells despite the resynthesis of IkappaB-alpha protein and (2) that inhibition of the transactivating activity of NF-kappaB by corticosteroids can be dissociated from a rise in IkappaB-alpha protein. We investigated the role of IkappaB-alpha in mesangial cells using a phosphorothioate antisense oligonucleotide directed against the translational start point of IkappaB-alpha. If IkappaB-alpha does function as a negative feedback inhibitor in these cells, then reducing IkappaB-alpha levels should lead to an increase in NF-kappaB activity. We first demonstrated that IkappaB-alpha protein resynthesis following stimulation could be specifically reduced. We then showed that NF-kappaB DNA binding was not increased with antisense treatment following stimulation. Finally, NF- kappaB-dependent gene signalling after stimulation (determined through an NF-kappaB luciferase reporter and upregulation of the mRNA of known NF-kappaB-responsive genes MCP-1 and IkappaB-alpha) was reduced rather than increased. These data suggest that IkappaB-alpha does not form a negative autoregulatory loop for NF-kappaB in mesangial cells and may actually reduce NF-kappaB activity. This may have relevance to therapies directed at inhibition of NF-kappaB activity in mesangial cell diseases.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 3","pages":"144-51"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21656863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse.","authors":"M P Cohen,&nbsp;N Masson,&nbsp;E Hud,&nbsp;F Ziyadeh,&nbsp;D C Han,&nbsp;R S Clements","doi":"10.1159/000020661","DOIUrl":"https://doi.org/10.1159/000020661","url":null,"abstract":"<p><p>Albumin modified by Amadori glucose adducts stimulates the expression of extracellular matrix proteins by glomerular mesangial and endothelial cells, and has been mechanistically linked to the pathogenesis of diabetic nephropathy. To test the hypothesis that inhibiting the formation of glycated albumin might beneficially influence the development of kidney disease in diabetes, we treated diabetic db/db mice for 12 weeks with a low-molecular-weight compound (EXO-226) that impedes the condensation of free glucose with lysine epsilon-amino groups in albumin. Administration of EXO-226 (3 mg/kg) twice daily by gavage normalized the plasma concentration of glycated albumin within days after initiation of treatment and maintained glycated albumin within the normal range throughout the study, despite persistent and severe hyperglycemia. Urine albumin excretion, which was markedly increased at the start of the study (age 12 weeks), was significantly reduced in treated diabetic animals compared with their untreated diabetic littermates. The fall in creatinine clearance that was observed in untreated diabetic animals was prevented in diabetic littermates that received treatment. Compared with the nondiabetic controls, the amount of glomerular mesangial matrix was threefold greater in untreated diabetic mice; in contrast, the mesangial matrix fraction was only 1. 5 times that of nondiabetic controls in the treated diabetic animals, representing a reduction in mesangial matrix accumulation of more than 50%. EXO-226 also reduced the overexpression of mRNA encoding for alpha1 (IV) collagen in renal cortex of db/db mice. We conclude that normalization of plasma glycated albumin concentrations with the glycation inhibitor EXO-226 ameliorates the glomerular structural and functional abnormalities associated with diabetic nephropathy in the db/db mouse.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 3","pages":"135-43"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21656864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic ureteral obstruction in the rat suppresses renal tubular Bcl-2 and stimulates apoptosis.","authors":"R L Chevalier,&nbsp;C D Smith,&nbsp;J Wolstenholme,&nbsp;S Krajewski,&nbsp;J C Reed","doi":"10.1159/000020657","DOIUrl":"https://doi.org/10.1159/000020657","url":null,"abstract":"<p><p>Unilateral ureteral obstruction (UUO) results in widespread tubular apoptosis in obstructed kidneys of both adults and neonates. The oncoprotein bcl-2 inhibits many forms of apoptosis, whereas the related protein bax promotes apoptosis. To evaluate the interaction of bcl-2, bax, and apoptosis in the renal response to UUO, adult and neonatal rats were subjected to UUO or sham operation, and kidneys were harvested 14 days later. Apoptotic cells were identified by the Tunel technique, and the distribution of bcl-2 and bax was determined by immunochemistry. In both adults and neonates, tubular and interstitial apoptosis was present in the obstructed kidney, but not in intact kidneys. In both adults and neonates, there was diffuse tubular bcl-2 and bax staining of sham-operated and intact kidneys. While bcl-2 was increased in scattered nonapoptotic tubules of the obstructed kidney, there was minimal staining of dilated apoptotic tubules. These results are consistent with the premise that bcl-2 normally suppresses renal tubular apoptosis. The distribution of bax staining in tubules of the obstructed kidney overlapped that of bcl-2. We conclude that chronic UUO inhibits bcl-2 expression in selected tubules of the obstructed kidney which contributes to activation of apoptosis and progressive renal damage in either neonatal or adult kidneys. Dysregulation of apoptosis may be a response to renal injury similar to that underlying the development of cystic kidney disease or renal dysplasia.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 2","pages":"115-22"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21581594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment with mycophenolate mofetil attenuates the development of Heymann nephritis.","authors":"M E Luca,&nbsp;L C Paul,&nbsp;A M van Der Wal,&nbsp;J A Bruijn,&nbsp;E de Heer","doi":"10.1159/000020652","DOIUrl":"https://doi.org/10.1159/000020652","url":null,"abstract":"<p><p>Active Heymann nephritis in the rat is a model of idiopathic membranous glomerulopathy in man. The autoimmune response is directed to gp330, a large epithelial glycoprotein that is expressed on the tubular and the glomerular epithelium. Characteristic of the disease is the presence of immune complexes and complement in the glomerulus and proteinuria. We studied the effect of a new xenobiotic immunosuppressive agent, mycophenolate mofetil, on active Heymann nephritis. Mycophenolate mofetil significantly reduced the production of autoantibodies against gp330 in rats with Heymann nephritis. Glomerular deposition of IgG was not significantly lower in the treated groups than in the untreated groups with active Heymann nephritis, as detected by immunofluorescence staining. Glomerular complement component C3, however, was significantly lower in the mycophenolate mofetil treated rats. Treatment did not completely prevent the disease, but the percentage of rats that developed proteinuria in the treated groups was significantly lower than in untreated Heymann rats. The results of this study show that mycophenolate mofetil influences the T-cell-mediated humoral autoimmune response in active Heymann nephritis and results in a decreased severity of the disease.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 2","pages":"77-83"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020652","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21580572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The number of nephrons in the mammalian kidney: environmental influences play a determining role.","authors":"M Lelièvre-Pégorier,&nbsp;C Merlet-Bénichou","doi":"10.1159/000020649","DOIUrl":"https://doi.org/10.1159/000020649","url":null,"abstract":"<p><p>Several lines of evidence, mostly derived from animal studies, indicate that changes in the fetal environment may affect the renal development. Fetal growth retardation is associated with a nephron deficit in both humans and animals. Changes in the supply of vitamin A to the fetus may be responsible for the variations in the number of nephrons in the human kidney. In utero exposure to hyperglycemia or drugs may also cause a nephron deficit.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 2","pages":"63-5"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020649","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21580569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidant enzyme gene expression in rats with remnant kidney induced chronic renal failure.","authors":"C Van Den Branden,&nbsp;B Ceyssens,&nbsp;D De Craemer,&nbsp;P De Bleser,&nbsp;K Hellemans,&nbsp;A Geerts,&nbsp;D Verbeelen","doi":"10.1159/000020654","DOIUrl":"https://doi.org/10.1159/000020654","url":null,"abstract":"<p><p>Reactive oxygen intermediates play a role in chronic renal injury and glomerulosclerosis. We investigate changes in renal cortex antioxidant enzyme gene expression in the rat remnant-kidney model of chronic renal failure and compare the new data to enzyme activities published earlier. Antioxidant enzyme gene expression is evaluated by Northern blot analysis of cortex mRNA, using cDNA probes for catalase, copper/zinc-containing superoxide dismutase, and glutathione peroxidase. Catalase gene expression decreases during development of renal failure; this decrease is accompanied by decreased catalase activity during the glomerulosclerosis phase of the remnant-kidney model. Copper/zinc superoxide dismutase and glutathione peroxidase gene expression remain at a normal level during progression of the model, whereas their activities show a temporary decrease in the early remnant kidney. In the remnant-kidney model, catalase seems to be more vulnerable to reactive oxygen intermediates than superoxide dismutase and glutathione peroxidase. Our results show that antioxidant enzyme activity and gene expression do not change in the same direction at all times during disease development and that all antioxidant enzymes do not respond in the same way.</p>","PeriodicalId":12179,"journal":{"name":"Experimental nephrology","volume":"8 2","pages":"91-6"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000020654","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21581679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}