Angiotensin Receptor Blocker Protection Against Podocyte-Induced Sclerosis Is Podocyte Angiotensin II Type 1 Receptor-Independent

In the present study, we tested the hypothesis that the renoprotective effect of an angiotensin receptor blocker depends on the angiotensin II type 1 (AT(1)) receptor on podocytes. For this purpose, we generated podocyte-specific knockout mice for the AT(1) gene (Agtr1a) and crossed with NEP25, in which selective podocyte injury can be induced by immunotoxin, anti-Tac(Fv)-PE38. Four weeks after the addition of anti-Tac(Fv)-PE38, urinary albumin: creatinine ratio was not attenuated in Agtr1a knockout/NEP25 mice (n = 18) compared with that in control NEP25 mice (n = 13; 8.08 +/- 2.41 in knockout versus 4.84 +/- 0.73 in control). Both strains of mice showed similar degrees of sclerosis (0.66 +/- 0.17 versus 0.82 +/- 0.27 on a 0 to 4 scale) and downregulation of nephrin (5.78 +/- 0.45 versus 5.65 +/- 0.58 on a 0 to 8 scale). In contrast, AT(1) antagonist or an angiotensin I-converting enzyme inhibitor, but not hydralazine, remarkably attenuated proteinuria and sclerosis in NEP25 mice. Moreover, continuous angiotensin II infusion induced microalbuminuria similarly in both Agtr1a knockout and wild-type mice. Thus, angiotensin inhibition can protect podocytes and prevent the development of glomerulosclerosis independent of podocyte AT(1). Possible mechanisms include inhibitory effects on AT(1) of other cells or through mechanisms independent of AT(1). Our study further demonstrates that measures that directly affect only nonpodocyte cells can have beneficial effects even when sclerosis is triggered by podocyte-specific injury. (Hypertension. 2010;55:967-973.)