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

¹Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558; ²Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki 701-01; and ³Department of Medicine II, Kansai Medical School, Osaka 570-8506, Japan

Submitted 21 August 2003 ; accepted in final form 20 October 2003

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 nephrectomy (Nx). AT₂R transgenic mice (AT₂-Tg), overexpressing AT₂R under the control of -smooth muscle actin (-SMA) promoter, and control wild-type mice (Wild) were subjected to Nx. In AT₂-Tg mice, the glomerular expression of AT₂R was upregulated after Nx. Urinary albumin excretion at 12 wk after Nx 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 Nx (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-₁ (TGF-₁) in AT₂-Tg with Nx 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-₁, was decreased in AT₂-Tg mice. These changes in AT₂-Tg mice at 12 wk after Nx were blocked by the AT₂R antagonist PD-123319. Taken together, our findings suggest that AT₂R-mediated signaling may protect from glomerular injuries induced by Nx and that overexpression of AT₂R may serve as a potential therapeutic strategy for glomerular disorders.

angiotensin II receptor; angiotensin II; transgenic mouse; nitric oxide

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