Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis

作者：Naito Takashi; Ma Li Jun; Yang Haichun; Zuo Yiqin; Tang Yiwei; Han Jee Young; Kon Valentina; Fogo Agnes B^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2010, 298(3): F683-F691.

DOI：10.1152/ajprenal.00503.2009

• podocyte
• plasminogen activator inhibitor-1

Naito T, Ma L-J, Yang H, Zuo Y, Tang Y, Han JY, Kon V, Fogo AB. Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis. Am J Physiol Renal Physiol 298: F683-F691, 2010. First published December 30, 2009; doi:10.1152/ajprenal.00503.2009.-Angiotensin type 1 (AT(1)) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT(1), or whether diversion of angiotensin II from the AT(1) to the available AT(2) receptor, thus potentially enhancing AT(2) receptor effects, is not known. We therefore investigated the role of AT(2) receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT(2) receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT(2) receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT(2) receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT(2) receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT(2) receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT(2) receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT(1) vs. AT(2) blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT(2) receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT(1) receptor, but also by increasing angiotensin effects transduced through the AT(2) receptor.

• 出版日期2010-3