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 AT1R. The aim of the present study was to determine the effect of AT2R overexpression on glomerular injury induced by 5/6 nephrectomy (5/6Nx). 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 5/6Nx. In AT(2)-Tg mice, the glomerular expression of AT(2)R was upregulated after 5/6Nx. Urinary albumin excretion at 12 wk after 5/6Nx 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 5/6Nx (93.1 +/- 3.0 vs. 103.3 +/- 1.8 mum; 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 5/6Nx 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 5/6Nx 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 5/6Nx and that overexpression of AT(2)R may serve as a potential therapeutic strategy for glomerular disorders.