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

Naoko Hashimoto, Yohei Maeshima, Minoru Satoh, Masahiro Odawara, Hitoshi Sugiyama, Naoki Kashihara, Hiroaki Matsubara, Yasushi Yamasaki, Hirofumi Makino

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume286
Issue number3 55-3
Publication statusPublished - Mar 2004

Fingerprint

Angiotensin Type 2 Receptor
Kidney
Wounds and Injuries
Transgenic Mice
Transforming Growth Factors
Nephrectomy
Angiotensin II
Smooth Muscle
Disease Progression
Actins
Albumins
Nitric Oxide
Immunohistochemistry
Cell Proliferation

Keywords

  • Angiotensin II
  • Angiotensin II receptor
  • Nitric oxide
  • Transgenic mouse

ASJC Scopus subject areas

  • Physiology

Cite this

Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model. / Hashimoto, Naoko; Maeshima, Yohei; Satoh, Minoru; Odawara, Masahiro; Sugiyama, Hitoshi; Kashihara, Naoki; Matsubara, Hiroaki; Yamasaki, Yasushi; Makino, Hirofumi.

In: American Journal of Physiology - Renal Physiology, Vol. 286, No. 3 55-3, 03.2004.

Research output: Contribution to journalArticle

Hashimoto, Naoko ; Maeshima, Yohei ; Satoh, Minoru ; Odawara, Masahiro ; Sugiyama, Hitoshi ; Kashihara, Naoki ; Matsubara, Hiroaki ; Yamasaki, Yasushi ; Makino, Hirofumi. / Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model. In: American Journal of Physiology - Renal Physiology. 2004 ; Vol. 286, No. 3 55-3.
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AU - Maeshima, Yohei

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AU - Sugiyama, Hitoshi

AU - Kashihara, Naoki

AU - Matsubara, Hiroaki

AU - Yamasaki, Yasushi

AU - Makino, Hirofumi

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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.

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