Protective effect of oral L-arginine supplementation on cyclosporine induced nephropathy in rats
Protective effect of oral L-arginine supplementation on cyclosporine induced nephropathy in rats
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DOI：
10.1007/s11255-004-0011-5
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发表时间：
2005-09-01
影响因子：
2
通讯作者：
Ozturk, Feral
中科院分区：
文献类型：
--
作者：
Kurus, Meltem;Esrefoglu, Mukaddes;Ozturk, Feral
背景：长期服用环孢菌素A（CyA）的主要不良反应之一是慢性肾毒性。一些研究表明，L-精氨酸（L-Arg）一氧化氮（NO）通路的改变可能参与CyA诱导的肾损伤的发病机制。目的：我们推测，在体内激活L-Arg-NO通路可能对CyA诱导的肾损伤具有有益作用。用L-Arg补充和用N-硝基-L-Arg甲酯（L-NAME）慢性NO阻断建立慢性NO增强的条件。我们验证了这样的假设，即如果CyA给药改变了肾内NO的合成，那么外源性L-Arg补充可以限制肾损伤，相反，L-NAME，一种有效的竞争性NO合成抑制剂，可以增强CyA的肾毒性。NO阻断的有害作用间接支持NO在CyA肾毒性模型中的有益作用。研究方法：实验结束时处死大鼠，分别给予溶媒（VH）、CyA（7.5mg/kg/d）、CyA + L-Arg（2g/kg/d）、CyA + L-NAME（5 mg/100 ml/d）、CyA + L-Arg + L-NAME、VH + L-Arg、VH + L-NAME。测定体重、血肌酐、血尿素氮（BUN）和一氧化氮（NO）水平。采用苏木精/伊红（H/E）、Masson三色和高碘酸-希夫（PAS）染色的石蜡切片上的评分系统半定量评价肾小管损伤和间质纤维化。结果如下：CyA组出现明显的肾损伤，其特征为血清肌酐和BUN显著升高，以及组织病理学改变，包括肾小管扩张、空泡化、坏死、间质细胞浸润和肾小管间质纤维化。CyA降低血清NO水平。L-Arg处理显著增强NO的生物合成，并保护动物免受CyA诱导的肾损伤。而L-NAME则显著降低血清NO水平，加重生化和组织病理学改变.结论：慢性CyA肾毒性可通过NO阻断而加重，并通过NO增强而改善，这表明补充L-Arg可能对CyA肾毒性具有保护作用。
Background: One of the major adverse effects of long term cyclosporine A ( CyA) administration is chronic nephrotoxicity. Several studies have suggested that alterations of the L-arginine (L-Arg) nitric oxide ( NO) pathway may be involved in the pathogenesis of CyA-induced kidney damage. Aim: We postulated that in vivo activation of L-Arg-NO pathway might have a beneficial effect on CyA-induced renal damage. Conditions of chronic NO enhancement was established with L-Arg supplementation and chronic NO blockade with N-nitro-L-Arg methyl ester ( L- NAME). We tested the hypothesis that, if CyA administration alters intrarenal NO synthesis, then exogenous L-Arg supplementation could limit renal injury, on the contrary, L- NAME, a potent competitive inhibitor of NO synthesis, could enhance CyA nephrotoxicity. Harmful effect of NO blockade indirectly supports the beneficial effect of NO in a model of CyA nephrotoxicity. Methods: Rats were administered vehicle (VH), CyA (7.5 mg/kg/day), CyA + L-Arg (2g/kg/day), CyA + L- NAME (5 mg/100ml/day), CyA + L-Arg + L- NAME, VH + L-Arg, VH + L-NAME and were sacrificed at the end of the experiment. Body weight, serum creatinine, blood urea nitrogen ( BUN) and NO levels were determined. Tubular injury and interstitial fibrosis were evaluated semiquantitatively using scoring systems on paraffin sections stained with hematoxylin/eosin (H/E), Masson's trichromic and periodic acid-Schiff (PAS). Results: The CyA group developed marked renal injury, characterized by a significant increase in serum creatinine and BUN, and histopathological alterations including tubular dilatation, vacuolization, necrosis, interstitial cell infiltration and tubulointerstitial fibrosis. CyA reduced serum NO level. L-Arg treatment significantly enhanced NO biosynthesis and protected animals from CyA-induced kidney damage. In contrast L- NAME strikingly reduced serum NO level, and worsened biochemical and histopathological alterations. Conclusion: Chronic CyA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement suggesting that L-Arg supplementation may be protective in CyA nephrotoxicity.