Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
Nephrol Dial Transplant. 2010 Nov;25(11):3518-25. doi: 10.1093/ndt/gfq272. Epub 2010 May 19.
The fawn-hooded hypertensive (FHH) rat develops spontaneous glomerulosclerosis that is ameliorated by inhibition of the angiotensin II type 1 receptor (AT-1). Since kidney damage is associated with nitric oxide (NO) deficiency, we investigated how AT-1 antagonism influenced nitric oxide synthase (NOS), as well as NOS substrate [L-arginine (L-Arg)] and inhibitor [asymmetric dimethylarginine (ADMA)]. L-Arg is synthesized by renal argininosuccinate synthase/argininosuccinate lyase (ASS/ASL) and then either consumed within the kidney by arginase II or NOS or released into the circulation. L-Arg is then taken up from plasma into cells where it can be utilized by NOS and other pathways. The competitive inhibitor of NOS, ADMA, is degraded by dimethylarginine dimethylaminohydrolase (DDAH).
Male FHH rats were put on a 40% casein diet for 13 weeks, and some received AT-1 antagonist which reduced blood pressure and kidney weight and prevented glomerulosclerosis and hyperfiltration. The AT-1 antagonist reduced the expression of DDAH2, increased DDAH1 and increased total DDAH activity in the kidney cortex, although there was no change in plasma or kidney cortex ADMA levels. The AT-1 antagonist caused no change in the expression of renal ASS/ASL, but reduced renal and aortic arginase expression and renal arginase activity, which could explain the increased plasma L-Arg. In separate studies, 1 week of AT-1 blockade in young FHH rats had no effect on any of these parameters.
Thus, the net result of AT-1 antagonist was an improved L-Arg to ADMA ratio due to the prevention of renal and vascular arginase activation which favours increased NO production. Since 1 week of AT-1 blockade in the absence of kidney damage was without effect on arginases, this suggests that the reduction in arginase activity is secondary to the prevention of structural damage rather than a direct immediate effect of AT-1 antagonism.
小鹿色高血压（FHH）大鼠会自发发展为肾小球硬化，而血管紧张素 II 型 1 型受体（AT-1）的抑制可改善该疾病。由于肾脏损伤与一氧化氮（NO）缺乏有关，我们研究了 AT-1 拮抗作用如何影响一氧化氮合酶（NOS），以及 NOS 底物[L-精氨酸（L-Arg）]和抑制剂[不对称二甲基精氨酸（ADMA）]。L-Arg 由肾脏精氨酸琥珀酸合成酶/精氨酸琥珀酸裂解酶（ASS/ASL）合成，然后在肾脏内被精氨酸酶 II 或 NOS 消耗，或者释放到循环中。然后，L-Arg 从血浆中被摄取到细胞内，在细胞内可以被 NOS 和其他途径利用。NOS 的竞争性抑制剂 ADMA 由二甲基精氨酸二甲氨基水解酶（DDAH）降解。
雄性 FHH 大鼠接受 40%酪蛋白饮食 13 周，部分大鼠接受 AT-1 拮抗剂治疗，可降低血压和肾脏重量，并预防肾小球硬化和高滤过。AT-1 拮抗剂降低了肾脏皮质中的 DDAH2 表达，增加了 DDAH1 和总 DDAH 活性，尽管血浆或肾脏皮质 ADMA 水平没有变化。AT-1 拮抗剂对肾脏 ASS/ASL 的表达没有影响，但降低了肾脏和主动脉的精氨酸酶表达和肾脏精氨酸酶活性，这可以解释血浆 L-Arg 的增加。在单独的研究中，1 周的 AT-1 阻断对年轻 FHH 大鼠的这些参数没有影响。
因此，AT-1 拮抗剂的净结果是由于预防了肾脏和血管精氨酸酶的激活，从而有利于增加 NO 的产生，使 L-Arg 与 ADMA 的比值得到改善。由于在没有肾脏损伤的情况下，1 周的 AT-1 阻断对精氨酸酶没有影响，这表明精氨酸酶活性的降低是结构损伤的继发结果，而不是 AT-1 拮抗作用的直接即时影响。
