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Angiotensin II type 1 receptor-associated protein deletion combined with angiotensin II stimulation accelerates the development of diabetic kidney disease in mice on a C57BL/6 strain

Hypertension Research volume 47, pages 55–66 (2024)Cite this article

Abstract

The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R and selectively inhibits pathological AT1R signaling. In this study, we investigated whether overactivation of the renin-angiotensin system (RAS) through a combination of ATRAP deletion with Ang II stimulation developed a progressive DKD model in C57BL/6 mice, which are resistant to the development of kidney injury. Eight-week-old male systemic ATRAP-knockout mice on the C57BL/6 strain (KO) and their littermate wild-type mice (Ctrl) were divided into five groups: 1) Ctrl, 2) Ctrl-streptozotocin (STZ), 3) KO-STZ, 4) Ctrl-STZ-Ang II, and 5) KO-STZ-Ang II. Ang II was administered for 6 weeks from 4 weeks after STZ administration. At 10 weeks after STZ administration, mice were euthanized to evaluate kidney injuries. Neither ATRAP deletion alone nor Ang II stimulation alone developed a progressive DKD model in STZ-induced diabetic C57BL/6 mice. However, a combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD as manifested by overt albuminuria, glomerular hypertrophy, podocyte loss, mesangial expansion, kidney interstitial fibrosis and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. In STZ-induced diabetic C57BL/6 mice that are resistant to the development of kidney injury, the combination of ATRAP deletion and Ang II stimulation accelerates the development of DKD, which may be associated with intrarenal RAS overactivation.

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Data availability

All relevant data are included within the paper. The datasets are available from the corresponding authors upon reasonable request.

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Acknowledgements

The authors are grateful to Prof. Thomas M. Coffman (Duke-NUS Medical School, Duke University School of Medicine) for useful discussions. We also thank Editage for editing and reviewing the English in this manuscript.

Funding

This work was supported by grants from the Yokohama Foundation for Advancement of Medical Science; Uehara Memorial Foundation; Japan Society for the Promotion of Science; Japan Kidney Association-Nippon Boehringer Ingelheim Joint Research Program; Japanese Association of Dialysis Physicians; Salt Science Research Foundation; Strategic Research Project of Yokohama City University; Japan Agency for Medical Research and Development (AMED); Translational Research program; Strategic Promotion for Practical Application of Innovative Medical Technology (TR-SPRINT) from AMED; Moriya Scholarship Foundation; Bayer Scholarship for Cardiovascular Research; and Mochida Memorial Foundation for Medical and Pharmaceutical Research.

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Authors and Affiliations

  1. Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Shinya Taguchi, Kengo Azushima, Takahiro Yamaji, Toru Suzuki, Eriko Abe, Shohei Tanaka, Keigo Hirota, Shunichiro Tsukamoto, Ryutaro Morita, Ryu Kobayashi, Sho Kinguchi, Hiromichi Wakui & Kouichi Tamura

  2. Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore

    Takahiro Yamaji

  3. Department of Investigative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan

    Akio Yamashita

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KA designed and conducted the research. STaguchi, KA, TY, AY, HW, and KT wrote the manuscript. STaguchi, KA, TS, EA, ST, KH, STsukamoto, RM, RK, SK, and HW performed the research. STaguchi and KA analyzed the data. KT supervised the research. All authors approved the final manuscript.

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Correspondence to Kengo Azushima or Hiromichi Wakui.

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Taguchi, S., Azushima, K., Yamaji, T. et al. Angiotensin II type 1 receptor-associated protein deletion combined with angiotensin II stimulation accelerates the development of diabetic kidney disease in mice on a C57BL/6 strain. Hypertens Res 47, 55–66 (2024). https://doi.org/10.1038/s41440-023-01496-4

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