A novel podocyte protein, R3h domain containing-like, inhibits TGF-β-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane

Journal of Molecular Medicine (2021)Cite this article

Abstract

Not only in kidney glomerular physiological function but also glomerular pathology especially in diabetic condition, glomerular podocytes play pivotal roles. Therefore, it is important to increase our knowledge about the genes and proteins expressed in podocytes. Recently, we have identified a novel podocyte-expressed gene, R3h domain containing-like (R3hdml) and analyzed its function in vivo as well as in vitro. Transforming growth factor-β (TGF-β) signaling regulated the expression of R3hdml. And R3hdml inhibited p38 mitogen-activated protein kinase phosphorylation, which was induced by TGF-β, leading to the amelioration of podocyte apoptosis. Furthermore, a lack of R3hdml in mice significantly worsened glomerular function in streptozotocin (STZ)-induced diabetes, while overexpression of R3hdml ameliorated albuminuria in STZ-induced diabetes. Our results surmise that the functional analyses of R3hdml may lead to the development of novel therapeutic strategies for diabetic nephropathy in the future.

Key messages

• A novel podocyte expressed protein R3h domain containing-like was identified.

• R3HDML inhibits podocyte apoptosis by inhibiting TGF-β-mediated p38 MAPK signaling.

• Overexpression of R3HDML ameliorates albuminuria in STZ-induced diabetes mice.

• R3HDML may prove to be a novel therapeutic strategy for diabetic nephropathy.

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Data availability

Data and material are available upon request to the corresponding author.

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Acknowledgements

We wish to thank Ms. Naoko Tomoda (Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine) for their valuable technical assistance and Ms. Sachie Matubara, and Ms. Junri Hayakawa (Laboratory for Electron Microscopy, Kyorin University School of Medicine) for the technical assistance with electron microscopy. This study is supported by the Grants-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labor and Welfare.

Contribution statement

T.I. performed most experiments. T.I., M.T., K.T., C.B., K.Y. conceived the ideas, designed the research. M.T. wrote the manuscript. Y.A. performed electro microscopic analysis. A.W., K.Y., K.S., Y.M., M.S., L.H.., K.T., C.B. assisted the experiments and statistics. Y.K. edited the manuscript. All authors discussed the results and commented on the manuscript.

Funding

This study is supported by the Grants-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labor and Welfare.

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Affiliations

  1. Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan

    Takahiro Ishikawa, Aki Takada-Watanabe, Kenichi Sakamoto, Yoshiro Maezawa & Koutaro Yokote

  2. Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, 4-3, Kozunomori, Narita, Chiba, 286-8686, Japan

    Minoru Takemoto

  3. Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

    Yoshihiro Akimoto

  4. Department of Pediatrics, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

    Kunimasa Yan

  5. Aichi Cancer Center Research Institute, Nagoya, Japan

    Miyuki Suguro

  6. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Liqun He & Christer Betsholtz

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

    Karl Tryggvason

  8. Department of Medicine Huddinge, Karolinska Institutet, Campus Flemingsberg, SE-141 57, Huddinge, Sweden

    Christer Betsholtz

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  1. Takahiro Ishikawa
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  2. Minoru Takemoto
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  3. Yoshihiro Akimoto
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  4. Aki Takada-Watanabe
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  11. Christer Betsholtz
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  12. Koutaro Yokote
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Correspondence to Minoru Takemoto.

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Ishikawa, T., Takemoto, M., Akimoto, Y. et al. A novel podocyte protein, R3h domain containing-like, inhibits TGF-β-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane. J Mol Med (2021). https://doi.org/10.1007/s00109-021-02050-w

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Keywords

  • Apoptosis
  • Diabetic nephropathy
  • Podocyte
  • p38mapk
  • TGF-β