Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model.

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT(1)R). Recent studies have suggested that type 2 receptor (AT(2)R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT(1)R. The aim of the present study was to determine the effect of AT(2)R overexpression on glomerular injury induced by (5/6) nephrectomy ((5/6)Nx). AT(2)R transgenic mice (AT(2)-Tg), overexpressing AT(2)R under the control of alpha-smooth muscle actin (alpha-SMA) promoter, and control wild-type mice (Wild) were subjected to (5/6)Nx. In AT(2)-Tg mice, the glomerular expression of AT(2)R was upregulated after (5/6)Nx. Urinary albumin excretion at 12 wk after (5/6)Nx was decreased by 33.7% in AT(2)-Tg compared with Wild mice. Glomerular size in AT(2)-Tg mice was significantly smaller than in Wild mice after (5/6)Nx (93.1 +/- 3.0 vs. 103.3 +/- 1.8 microm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-beta(1) (TGF-beta(1)) in AT(2)-Tg with (5/6)Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT(2)-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-beta(1), was decreased in AT(2)-Tg mice. These changes in AT(2)-Tg mice at 12 wk after (5/6)Nx were blocked by the AT(2)R antagonist PD-123319. Taken together, our findings suggest that AT(2)R-mediated signaling may protect from glomerular injuries induced by (5/6)Nx and that overexpression of AT(2)R may serve as a potential therapeutic strategy for glomerular disorders.