TY - JOUR
T1 - Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model
AU - Hashimoto, Naoko
AU - Maeshima, Yohei
AU - Satoh, Minoru
AU - Odawara, Masahiro
AU - Sugiyama, Hitoshi
AU - Kashihara, Naoki
AU - Matsubara, Hiroaki
AU - Yamasaki, Yasushi
AU - Makino, Hirofumi
PY - 2004/3
Y1 - 2004/3
N2 - 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 5/6 nephrectomy (5/6Nx). AT2R transgenic mice (AT 2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to 5/6Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after 5/6Nx. Urinary albumin excretion at 12 wk after 5/6Nx 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 5/6Nx (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-β 1) in AT2-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-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after 5/6Nx were blocked by the AT 2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by 5/6Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.
AB - 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 5/6 nephrectomy (5/6Nx). AT2R transgenic mice (AT 2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to 5/6Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after 5/6Nx. Urinary albumin excretion at 12 wk after 5/6Nx 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 5/6Nx (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-β 1) in AT2-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-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after 5/6Nx were blocked by the AT 2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by 5/6Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.
KW - Angiotensin II
KW - Angiotensin II receptor
KW - Nitric oxide
KW - Transgenic mouse
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U2 - 10.1152/ajprenal.00294.2003
DO - 10.1152/ajprenal.00294.2003
M3 - Article
C2 - 14583437
AN - SCOPUS:1242351761
SN - 0363-6127
VL - 286
SP - F516-F525
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 3 55-3
ER -