Abstract
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.
