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The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats

Hypertension Research volume 46, pages 50–62 (2023)Cite this article

Abstract

Salt-sensitive hypertension is associated with poor clinical outcomes. The epithelial sodium channel (ENaC) in the kidney plays pivotal roles in sodium reabsorption and blood pressure regulation, in which its γ subunit is activated by extracellular serine proteases. In proteinuric nephropathies, plasmin filtered through injured glomeruli reportedly activates γENaC in the distal nephron and causes podocyte injury. We previously reported that Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet developed hypertension and proteinuria along with γENaC activation and that a synthetic serine protease inhibitor, camostat mesilate, mitigated these changes. However, the role of plasmin in DS rats remained unclear. In this study, we evaluated the relationship between plasmin and hypertension as well as podocyte injury and the effects of plasmin inhibitors in DS rats. Five-week-old DS rats were divided into normal-salt diet, HS diet, and HS+plasmin inhibitor (either tranexamic acid [TA] or synthetic plasmin inhibitor YO-2) groups. After blood pressure measurement and 24 h urine collection over 5 weeks, rats were sacrificed for biochemical analyses. The HS group displayed severe hypertension and proteinuria together with activation of plasmin in urine and γENaC in the kidney, which was significantly attenuated by YO-2 but not TA. YO-2 inhibited the attachment of plasmin(ogen) to podocytes and alleviated podocyte injury by inhibiting apoptosis and inflammatory/profibrotic cytokines. YO-2 also suppressed upregulation of protease-activated receptor-1 and phosphorylated ERK1/2. These results indicate an important role of plasmin in the development of salt-sensitive hypertension and related podocyte injury, suggesting plasmin inhibition as a potential therapeutic strategy.

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Acknowledgements

Q. Deng was supported by the Otsuka Toshimi Scholarship Foundation, which has enabled him to complete this project successfully. We appreciate Ms. Naoko Hirano and Kazumi Saito for their technical assistance and Ms. Noriko Nakagawa and Miki Horikiri for their secretarial assistance. The Graphical Abstract was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (https://smart.servier.com).

Funding

This work was supported by the Grants-in-Aid for Scientific Research KAKENHI from Japan Society for the Promotion of Science (20K17250 to T. Nakagawa and 17K09705 to Y. Kakizoe) and the Salt Science Research Foundation (20C3 to Y. Kakizoe).

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Authors and Affiliations

  1. Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

    Qinyuan Deng, Yutaka Kakizoe, Yasunobu Iwata, Terumasa Nakagawa, Yoshikazu Miyasato, Miyuki Nakagawa, Kayo Nishiguchi, Yu Nagayoshi, Masataka Adachi, Yuichiro Izumi, Takashige Kuwabara & Masashi Mukoyama

  2. Comprehensive Clinical Education, Training and Development Center, Kumamoto University Hospital, Kumamoto, Japan

    Yutaka Kakizoe & Masashi Mukoyama

  3. Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan

    Yuki Narita

  4. The Faculty of Pharmaceutical Science, Kobe Gakuin University, Kobe, Japan

    Yuko Tsuda

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  1. Qinyuan Deng
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Deng, Q., Kakizoe, Y., Iwata, Y. et al. The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats. Hypertens Res 46, 50–62 (2023). https://doi.org/10.1038/s41440-022-01064-2

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