Clinical and experimental nephrology · 2017
Arterial wall hypertrophy is ameliorated by α2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice.
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Nakamori Haruka, Yoshida Shin-Ichiro, Ishiguro Hiroaki, Suzuki Shota, Yasuzaki Hiroaki, Hashimoto Tatsuo, Ishigami Tomoaki, Hirawa Nobuhito, Toya Yoshiyuki, Umemura Satoshi, Tamura Kouichi
Аннотация
BACKGROUND: Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg -/-) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-β1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-β1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required.
METHODS: We performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg -/- mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-β1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis.
RESULTS: Norepinephrine content in kidneys of Atg -/- mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-β1 gene in kidneys of Atg -/- mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced α2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg -/- mice, which lack renin substrate.
CONCLUSIONS: Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg -/- mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of α2-ARs. Although renal arterial hypertrophy in Atg -/- mice appears to be of multifactorial origin, TGF-β1 may play a key role in the persistence of such hypertrophy.
METHODS: We performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg -/- mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-β1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis.
RESULTS: Norepinephrine content in kidneys of Atg -/- mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-β1 gene in kidneys of Atg -/- mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced α2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg -/- mice, which lack renin substrate.
CONCLUSIONS: Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg -/- mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of α2-ARs. Although renal arterial hypertrophy in Atg -/- mice appears to be of multifactorial origin, TGF-β1 may play a key role in the persistence of such hypertrophy.