Lassila M
Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, Finland.
Curr Drug Metab. 2002 Feb;3(1):61-71. doi: 10.2174/1389200023337964.
Despite extensive research, the exact mechanisms of cyclosporine A (CsA)-induced hypertension and nephrotoxicity remain obscure. Several lines of evidence suggest an involvement of the renin-angiotensin system (RAS) in CsA toxicity, but the issue is still controversial in more ways than one. Some interesting data of the interaction of CsA and RAS have been presented by us and others during the last years. In rats, activation of RAS by CsA is a consistent finding while the results from clinical studies show controversial results. The mechanisms of activation of RAS may be multifactorial. CsA increases renin release directly from juxtaglomerular cells. However, RAS activation may at least partly account for glomerular ischemia by vasoconstriction. A totally different view about the interaction of CsA and RAS has recently been presented. CsA antagonised the harmful effects of RAS over-expression on renal damage in double transgenic rats harbouring human renin and angiotensinogen genes. The protection was due to anti-inflammatory properties of CsA by inhibition of interleukin-6 and inducible nitric oxide synthase (iNOS) expression. Other studies have confirmed the inhibitory effect of CsA on iNOS. Calcium antagonists have been proposed to be the antihypertensive drugs of choice in treatment of CsA-induced hypertension because of their favourable haemodynamic effects on the kidneys. However, because angiotensin II plays a major role in the development of CsA-induced structural renal damage, pharmacological inhibition of RAS in CsA-treatment may have some beneficial effects beyond blood pressure control.
尽管进行了广泛研究，但环孢素A（CsA）所致高血压和肾毒性的确切机制仍不清楚。有几条证据表明肾素-血管紧张素系统（RAS）参与了CsA毒性作用，但该问题在多个方面仍存在争议。在过去几年中，我们和其他研究人员已提出了一些有关CsA与RAS相互作用的有趣数据。在大鼠中，CsA激活RAS是一个一致的发现，而临床研究结果却存在争议。RAS激活的机制可能是多因素的。CsA可直接从肾小球旁细胞增加肾素释放。然而，RAS激活可能至少部分是通过血管收缩导致肾小球缺血。最近有人提出了关于CsA与RAS相互作用的完全不同的观点。在携带人肾素和血管紧张素原基因的双转基因大鼠中，CsA拮抗了RAS过表达对肾损伤的有害作用。这种保护作用归因于CsA通过抑制白细胞介素-6和诱导型一氧化氮合酶（iNOS）表达所具有的抗炎特性。其他研究已证实CsA对iNOS具有抑制作用。由于钙拮抗剂对肾脏具有良好的血流动力学效应，已有人提出将其作为治疗CsA所致高血压的首选降压药物。然而，由于血管紧张素II在CsA所致肾脏结构损伤的发生中起主要作用，在CsA治疗中对RAS进行药理抑制可能除了控制血压外还具有一些有益作用。
