Kuruş Meltem, Eşrefoğlu Mukaddes, Bay Aysun, Oztürk Feral
Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey.
Int Urol Nephrol. 2005;37(3):587-94. doi: 10.1007/s11255-004-0011-5.
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.
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.
Rats were administered vehicle (VH), CyA (7.5 mg/kg/day), CyA + L-Arg (2g/kg/day), CyA + L-NAME (5 mg/100 ml/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).
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.
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.
长期服用环孢素A（CyA）的主要不良反应之一是慢性肾毒性。多项研究表明，L-精氨酸（L-Arg）一氧化氮（NO）途径的改变可能参与了CyA诱导的肾损伤的发病机制。
我们推测，体内L-Arg-NO途径的激活可能对CyA诱导的肾损伤具有有益作用。通过补充L-Arg建立慢性NO增强的条件，并用N-硝基-L-精氨酸甲酯（L-NAME）进行慢性NO阻断。我们检验了以下假设：如果给予CyA会改变肾内NO的合成，那么外源性补充L-Arg可以限制肾损伤，相反，NO合成的强效竞争性抑制剂L-NAME会增强CyA的肾毒性。在CyA肾毒性模型中，NO阻断的有害作用间接支持了NO的有益作用。
给大鼠分别灌胃赋形剂（VH）、CyA（7.5 mg/kg/天）、CyA + L-Arg（2g/kg/天）、CyA + L-NAME（5 mg/100 ml/天）、CyA + L-Arg + L-NAME、VH + L-Arg、VH + L-NAME，实验结束时处死大鼠。测定体重、血清肌酐、血尿素氮（BUN）和NO水平。使用苏木精/伊红（H/E）、Masson三色染色和高碘酸-希夫（PAS）染色的石蜡切片评分系统对肾小管损伤和间质纤维化进行半定量评估。
CyA组出现明显的肾损伤，表现为血清肌酐和BUN显著升高，以及包括肾小管扩张、空泡化、坏死、间质细胞浸润和肾小管间质纤维化在内的组织病理学改变。CyA降低了血清NO水平。L-Arg治疗显著增强了NO的生物合成，并保护动物免受CyA诱导的肾损伤。相反，L-NAME显著降低了血清NO水平，并使生化和组织病理学改变恶化。
NO阻断可加重慢性CyA肾毒性，NO增强可改善慢性CyA肾毒性，提示补充L-Arg可能对CyA肾毒性具有保护作用。
