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Clinical and Experimental Nephrology

, Volume 22, Issue 4, pp 773–781 | Cite as

Arterial wall hypertrophy is ameliorated by α2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice

  • Haruka Nakamori
  • Shin-ichiro Yoshida
  • Hiroaki Ishiguro
  • Shota Suzuki
  • Hiroaki Yasuzaki
  • Tatsuo Hashimoto
  • Tomoaki Ishigami
  • Nobuhito Hirawa
  • Yoshiyuki Toya
  • Satoshi Umemura
  • Kouichi Tamura
Original article

Abstract

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.

Keywords

Angiotensinogen-knockout mouse Kidney Arterial hypertrophy Sympathetic nerve Aliskiren 

Notes

Acknowledgements

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.

Ethical statement

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).

Informed consent

In this study, informed consent was not required because any human sample was not used.

Supplementary material

10157_2017_1520_MOESM1_ESM.pdf (228 kb)
Supplementary material 1 (PDF 228 KB)

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Copyright information

© Japanese Society of Nephrology 2017

Authors and Affiliations

  • Haruka Nakamori
    • 1
  • Shin-ichiro Yoshida
    • 1
  • Hiroaki Ishiguro
    • 1
  • Shota Suzuki
    • 1
  • Hiroaki Yasuzaki
    • 1
  • Tatsuo Hashimoto
    • 1
  • Tomoaki Ishigami
    • 1
  • Nobuhito Hirawa
    • 1
  • Yoshiyuki Toya
    • 1
  • Satoshi Umemura
    • 1
  • Kouichi Tamura
    • 1
  1. 1.Department of Medical Science and Cardiorenal MedicineYokohama City University Graduate School of MedicineYokohamaJapan

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