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

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Abstract
Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT1R). Recent studies have suggested that type 2 receptor (AT2R)-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 ⅚ nephrectomy (⅚Nx). AT2R transgenic mice (AT2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to ⅚Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after ⅚Nx. Urinary albumin excretion at 12 wk after ⅚Nx was decreased by 33.7% in AT2-Tg compared with Wild mice. Glomerular size in AT2-Tg mice was significantly smaller than in Wild mice after ⅚Nx (93.1 ± 3.0 vs. 103.3 ± 1.8 μm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-β1(TGF-β1) in AT2-Tg with ⅚Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT2-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after ⅚Nx were blocked by the AT2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by ⅚Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.