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Role of intrarenal endothelin 1, endothelin 3, and angiotensin II expression in chronic cyclosporin A nephrotoxicity in rats. 肾内内皮素1、内皮素3和血管紧张素II表达在大鼠慢性环孢素A肾毒性中的作用。
Pub Date : 2000-05-01 DOI: 10.1159/000020664
C Ramírez, A Olmo, F O'Valle, M Masseroli, M Aguilar, M Gómez-Morales, F Revelles, M J García-Chicano, F Arrebola, M E Reguero, R G del Moral

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.

内皮素1 (Et1)在肾脏中广泛表达,与多种功能和向硬化发展的病理状况有关。内皮素3 (Et3)在肾脏水平上的功能尚存争议,但它可能通过作用于小管B型受体在水的重吸收中具有重要的调节功能。血管紧张素II最近被认为是环孢素A (CsA)诱导的间质纤维化进展的主要因素。我们在体内研究了这种关系,并分析了25 mg/kg/天CsA对Sprague-Dawley大鼠28和56天CsA毒性引起的修饰。采用免疫组织化学方法和分子分析方法研究Et1和Et3的表达,单独采用免疫组织化学方法测定肾内血管紧张素II的表达。经CsA处理的大鼠出现慢性肾毒性病变;半定量分析显示,时间的推移影响了这种病变的范围,导致肾小球总面积的减少。免疫组化结果显示,慢性CsA治疗诱导Et1和Et3在肾小管和肾小球水平适度分泌,治疗组血管紧张素II的局部表达比对照组更明显。此外,从CsA处理后28 d开始,preproEt3 mRNA水平显著升高(对照组0.07+/-0.11,CsA组0.48+/-0.11,p0.50, p0.50, p
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引用次数: 44
Cloning of rabbit Cct6 and the distribution of the Cct complex in mammalian tissues. 兔Cct6的克隆及Cct复合物在哺乳动物组织中的分布。
Pub Date : 2000-05-01 DOI: 10.1159/000020663
G J Schwartz, A M Kittelberger, G B Segel

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.

Cct6蛋白是参与atp依赖性细胞蛋白折叠的Cct复合体的亚基之一。我们利用人CCT6亚基cDNA从兔肾皮质文库中获得全长cDNA。在兔肾脏和肝脏中分别检测到2和2.5 kb的转录本。兔的CCT6基因与人类基因的一致性为93%;推导出的氨基酸序列有97%相同。对小鼠、兔、人和酵母的Cct6蛋白的系统发育分析表明,Cct6蛋白在物种之间的相似性大于其他Cct亚基。atp结合位点在哺乳动物和酵母中完全保守,支持Cct复合物在atp依赖性蛋白折叠中的作用。利用人Cct6蛋白的多克隆抗体和Western分析,我们发现该亚基在多种兔器官和组织、牛睾丸、人淋巴细胞、人和兔网织细胞以及两种培养的肾细胞系中都有表达。通过Western分析,我们还在兔的几个器官和牛的睾丸中发现了Cct1蛋白。这些数据表征了兔Cct6亚基,并将其与同源物进行了比较。西方的分析支持Cct复合体广泛分布于组织中,在真核生物中高度保守的观点。
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引用次数: 4
The molecular basis of cystinuria: an update. 胱氨酸尿的分子基础:最新进展。
Pub Date : 2000-05-01 DOI: 10.1159/000020659
P Goodyer, M Boutros, R Rozen

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.

胱氨酸尿症是一种遗传性疾病的胱氨酸和二碱性氨基酸运输通过肾近端小管和小肠管腔膜。1992年,从非洲爪蟾卵母细胞中分离到一段cDNA (rBAT),表达后可诱导高亲和力、不依赖钠的胱氨酸和双碱性氨基酸摄取。rBAT基因被定位到已知含有胱氨酸尿位点的2p染色体区域,rBAT在肾近端小管和小肠的直(S3)部分被证实表达。在遗传两种全隐性(I型)胱氨酸尿基因的患者中,已经描述了30多种不同的rBAT突变。最近,在染色体19q上发现了第二个胱氨酸尿基因(SLC7A9);SLC7A9突变被证明会导致不完全隐性的胱氨酸尿症(II型和III型)。遗传两个突变SLC7A9基因的患者复发性肾结石的几率与两个rBAT突变的患者相当。在一些胱氨酸尿症家族中,患者从父母一方遗传了完全隐性等位基因,从另一方遗传了不完全隐性等位基因;患有这种“混合型”胱氨酸尿症的患者病情较轻。目前尚不清楚这种形式的胱氨酸尿是否涉及rBAT和SLC7A9突变。目前的证据表明,在腔面介导胱氨酸和二碱性氨基酸摄取的跨膜通道是由SLC7A9编码的;较小的rBAT蛋白与该通道形成异二聚体复合物,对其靶向管腔膜至关重要。
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引用次数: 25
Arginase in glomerulonephritis. 精氨酸酶在肾小球肾炎中的作用。
Pub Date : 2000-05-01 DOI: 10.1159/000020660
S N Waddington, V Cattell

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.

精氨酸酶将l -精氨酸代谢为l -鸟氨酸和尿素。已经确定了两种精氨酸酶亚型,AI(肝精氨酸酶)和AII(普遍表达,功能未知)。很明显,精氨酸酶除了在炎症部位产生高浓度尿素外,还可能发挥重要作用。调节通过细胞因子、底物竞争和一氧化氮(NO)代谢产物发生。精氨酸酶在炎症部位的功能尚不清楚,但可能包括调节细胞凋亡和NO的产生以及结构和细胞蛋白前体的生成。在肾小球肾炎中,肾小球精氨酸酶活性增加,其模式与伤口愈合相似。NO抑制可进一步提高该水平,提示底物竞争。炎症肾小球的潜在来源包括浸润的白细胞和系膜细胞,主要表达的亚型是AI (AII在生理条件下占优势)。最近对精氨酸酶不同亚型的鉴定是了解精氨酸酶活性在肾小球肾炎中的意义的重要一步。
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引用次数: 21
Inhibition with antisense oligonucleotide suggests that IkappaB-alpha does not form a negative autoregulatory loop for NF-kappaB in mesangial cells. 反义寡核苷酸抑制表明ikappab - α在系膜细胞中不形成NF-kappaB的负自我调节环。
Pub Date : 2000-05-01 DOI: 10.1159/000020662
R B Auwardt, S J Mudge, C Chen, D A Power

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.

IkappaB蛋白在NF-kappaB/Rel组转录因子的调控中起重要作用,而NF-kappaB/Rel组转录因子在炎症反应中起关键作用。ikappab - α本身通过NF-kappaB的激活而上调,并被认为是负反馈回路的一部分。然而,ikappab - α的作用受到了挑战,最近的证据表明:(1)尽管ikappab - α蛋白重新合成,但系膜和内皮细胞中NF-kappaB的持续激活;(2)皮质类固醇对NF-kappaB反激活活性的抑制可以与ikappab - α蛋白的升高分离。我们利用针对ikappab - α翻译起始点的硫代反义寡核苷酸研究了ikappab - α在系膜细胞中的作用。如果ikappab - α确实在这些细胞中起负反馈抑制剂的作用,那么ikappab - α水平的降低应该会导致NF-kappaB活性的增加。我们首先证明刺激后ikappab - α蛋白的再合成可以特异性地减少。我们随后发现,刺激后的反义处理并没有增加NF-kappaB DNA结合。最后,刺激后NF- kappab依赖的基因信号传导(通过NF- kappab荧光素酶报告基因和已知NF- kappab应答基因MCP-1和ikappab - α mRNA的上调来测定)减少而不是增加。这些数据表明,IkappaB-alpha不会在系膜细胞中形成NF-kappaB的负自我调节环,实际上可能会降低NF-kappaB的活性。这可能与在系膜细胞疾病中抑制NF-kappaB活性的治疗有关。
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引用次数: 15
Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse. 抑制白蛋白糖化可改善db/db小鼠的糖尿病肾病。
Pub Date : 2000-05-01 DOI: 10.1159/000020661
M P Cohen, N Masson, E Hud, F Ziyadeh, D C Han, R S Clements

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.

Amadori葡萄糖加合物修饰的白蛋白刺激肾小球系膜细胞和内皮细胞细胞外基质蛋白的表达,并与糖尿病肾病的发病机制有关。为了验证抑制糖化白蛋白的形成可能有利于糖尿病肾脏疾病发展的假设,我们用一种低分子量化合物(EXO-226)治疗糖尿病db/db小鼠12周,这种化合物可以阻止白蛋白中游离葡萄糖与赖氨酸ε -氨基的冷凝。EXO-226 (3mg /kg)每天两次灌胃,在治疗开始后几天内使血浆糖化白蛋白浓度正常化,并在整个研究期间将糖化白蛋白维持在正常范围内,尽管存在持续和严重的高血糖。尿白蛋白排泄在研究开始时(12周龄)明显增加,与未治疗的糖尿病鼠相比,治疗后的糖尿病鼠尿白蛋白排泄明显减少。在未治疗的糖尿病动物中观察到的肌酐清除率的下降在接受治疗的糖尿病幼崽中得到了预防。与非糖尿病对照组相比,未经治疗的糖尿病小鼠肾小球系膜基质的数量增加了三倍;而系膜基质分数仅为1。治疗后的糖尿病动物是非糖尿病对照组的5倍,表明系膜基质积累减少了50%以上。EXO-226还降低了db/db小鼠肾皮质α 1 (IV)胶原编码mRNA的过表达。我们得出结论,糖基化抑制剂EXO-226使血浆糖化白蛋白浓度正常化,可改善db/db小鼠与糖尿病肾病相关的肾小球结构和功能异常。
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引用次数: 39
Chronic ureteral obstruction in the rat suppresses renal tubular Bcl-2 and stimulates apoptosis. 大鼠慢性输尿管梗阻抑制肾小管Bcl-2并刺激细胞凋亡。
Pub Date : 2000-03-01 DOI: 10.1159/000020657
R L Chevalier, C D Smith, J Wolstenholme, S Krajewski, J C Reed

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.

单侧输尿管梗阻(UUO)导致成人和新生儿肾脏梗阻中广泛的肾小管凋亡。癌蛋白bcl-2抑制多种形式的细胞凋亡,而相关蛋白bax促进细胞凋亡。为了评估bcl-2、bax和细胞凋亡在肾对UUO反应中的相互作用,我们对成年和新生大鼠进行UUO或假手术,并在14天后摘取肾脏。Tunel法检测凋亡细胞,免疫化学法检测bcl-2和bax的分布。在成人和新生儿中,肾小管和间质细胞凋亡存在于梗阻的肾脏中,而不存在于完整的肾脏中。在成人和新生儿中,假手术和完整肾脏均可见弥漫性肾小管bcl-2和bax染色。虽然bcl-2在梗阻肾的分散的非凋亡小管中升高,但扩张的凋亡小管染色很少。这些结果与bcl-2正常抑制肾小管凋亡的前提一致。bax染色在梗阻肾小管中的分布与bcl-2的分布重叠。我们得出结论,慢性UUO抑制梗阻肾小管中bcl-2的表达,这有助于激活新生儿或成人肾脏的细胞凋亡和进行性肾损伤。细胞凋亡的失调可能是对肾损伤的反应,类似于囊性肾病或肾发育不良的潜在发展。
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引用次数: 46
Treatment with mycophenolate mofetil attenuates the development of Heymann nephritis. 霉酚酸酯治疗可减轻海曼肾炎的发展。
Pub Date : 2000-03-01 DOI: 10.1159/000020652
M E Luca, L C Paul, A M van Der Wal, J A Bruijn, E de Heer

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.

大鼠活动性海曼肾炎是人类特发性膜性肾小球病的模型。自身免疫反应指向gp330,这是一种在肾小管上皮和肾小球上皮上表达的大的上皮糖蛋白。本病的特点是肾小球中存在免疫复合物和补体以及蛋白尿。我们研究了一种新的异种免疫抑制剂霉酚酸酯对活动性海曼肾炎的作用。霉酚酸酯显著降低海曼肾炎大鼠抗gp330自身抗体的产生。免疫荧光染色检测,治疗组活动性海曼肾炎的肾小球IgG沉积不明显低于未治疗组。然而,在霉酚酸酯治疗的大鼠中,肾小球补体成分C3明显降低。治疗并没有完全预防疾病,但治疗组发生蛋白尿的大鼠比例明显低于未治疗的海曼大鼠。本研究结果表明,霉酚酸酯影响活动性海曼肾炎中t细胞介导的体液自身免疫反应,并导致疾病严重程度降低。
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引用次数: 9
The number of nephrons in the mammalian kidney: environmental influences play a determining role. 哺乳动物肾脏中肾单位的数量:环境影响起决定性作用。
Pub Date : 2000-03-01 DOI: 10.1159/000020649
M Lelièvre-Pégorier, C Merlet-Bénichou

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.

一些主要来自动物研究的证据表明,胎儿环境的变化可能会影响肾脏的发育。在人类和动物中,胎儿生长迟缓都与肾元缺陷有关。胎儿维生素A供给的变化可能是人体肾脏中肾单位数量变化的原因。在子宫内暴露于高血糖或药物也可引起肾元缺陷。
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引用次数: 41
Antioxidant enzyme gene expression in rats with remnant kidney induced chronic renal failure. 残肾致慢性肾功能衰竭大鼠抗氧化酶基因的表达。
Pub Date : 2000-03-01 DOI: 10.1159/000020654
C Van Den Branden, B Ceyssens, D De Craemer, P De Bleser, K Hellemans, A Geerts, D Verbeelen

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.

活性氧中间体在慢性肾损伤和肾小球硬化中起作用。我们研究了慢性肾功能衰竭大鼠残肾模型中肾皮质抗氧化酶基因表达的变化,并将新数据与早期发表的酶活性进行了比较。利用过氧化氢酶、含铜/锌超氧化物歧化酶和谷胱甘肽过氧化物酶的cDNA探针,对皮质mRNA进行Northern blot分析,评估抗氧化酶基因的表达。过氧化氢酶基因表达在肾功能衰竭过程中降低;在残肾模型的肾小球硬化阶段,这种降低伴随着过氧化氢酶活性的降低。铜/锌超氧化物歧化酶和谷胱甘肽过氧化物酶基因表达在模型发展过程中保持正常水平,而其活性在早期残肾中出现暂时下降。在残肾模型中,过氧化氢酶似乎比超氧化物歧化酶和谷胱甘肽过氧化物酶更容易受到活性氧中间体的影响。我们的研究结果表明,在疾病发展过程中,抗氧化酶活性和基因表达并不是在同一方向上发生变化,所有的抗氧化酶也不是以相同的方式做出反应。
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引用次数: 16
期刊
Experimental nephrology
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