Arterial wall hypertrophy is ameliorated by α2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice
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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.
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.
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.
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.
KeywordsAngiotensinogen-knockout mouse Kidney Arterial hypertrophy Sympathetic nerve Aliskiren
We acknowledge Ms. Hiroko Morinaga and Ms. Emi Maeda, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine for technical assistance. S.Y. and S.U. received research funding from Novartis Pharmaceuticals.
Compliance with ethical standards
Conflict of interest
All authors declare no conflicts of interest.
Experiments were conducted under the guidelines for animal experiments set by the Animal Experiment Committee of Yokohama City University School of Medicine (Approval number F-A-14-042).
In this study, informed consent was not required because any human sample was not used.
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