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Roles of the mechanosensitive ion channel Piezo1 in the renal podocyte injury of experimental hypertensive nephropathy

Hypertension Research volume 47, pages 747–759 (2024)Cite this article

A Comment to this article was published on 09 February 2024

Abstract

Glomerular podocyte injury plays an essential role in proteinuria pathogenesis, a hallmark of chronic kidney disease, including hypertensive nephropathy. Although podocytes are susceptible to mechanical stimuli, their mechanotransduction pathways remain elusive. Piezo proteins, including Piezo1 and 2, are mechanosensing ion channels that mediate various biological phenomena. Although renal Piezo2 expression and its alteration in rodent dehydration and hypertension models have been reported, the role of Piezo1 in hypertensive nephropathy and podocyte injury is unclear. In this study, we examined Piezo1 expression and localization in the kidneys of control mice and in those of mice with hypertensive nephrosclerosis. Uninephrectomized, aldosterone-infused, salt-loaded mice developed hypertension, albuminuria, podocyte injury, and glomerulosclerosis. RNAscope in situ hybridization revealed that Piezo1 expression was enhanced in the podocytes, mesangial cells, and distal tubular cells of these mice compared to those of the uninephrectomized, vehicle-infused control group. Piezo1 upregulation in the glomeruli was accompanied by the induction of podocyte injury-related markers, plasminogen activator inhibitor-1 and serum/glucocorticoid regulated kinase 1. These changes were reversed by antihypertensive drug. Exposure of Piezo1-expressing cultured podocytes to mechanical stretch activated Rac1 and upregulated the above-mentioned markers, which was antagonized by the Piezo1 blocker grammostola mechanotoxin #4 (GsMTx4). Administration of Piezo1-specific agonist Yoda1 mimicked the effects of mechanical stretch, which was minimized by the Yoda1-specific inhibitor Dooku1 and Rac inhibitor. Rac1 was also activated in the above-mentioned hypertensive mice, and Rac inhibitor downregulated gene expression of podocyte injury-related markers in vivo. Our results suggest that Piezo1 plays a role in mechanical stress-induced podocyte injury.

The roles of mechanosensitive ion channel Piezo1 are unknown in hypertensive nephropathy and podocyte injury. We showed Piezo1 upregulation in podocytes together with their injury in hypertensive nephropathy mouse model. Mechanical stretch or Yoda1 administration in the cultured podocytes upregulated podocyte injury-related markers, further suggesting Piezo1 involvement in podocyte injury.

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Acknowledgements

We are grateful to Dr. Yuki Mochida and Dr. Koji Ochiai for their help with data analyses, to Prof. Hidetake Kurihra for providing the rat podocyte cell lines, to Prof. Yoshihiro Akimoto for his help with electron microscopy, and to Dr. Keiko Nonomura, Prof. Yoshihiro Yamaguchi, Prof. Hiroshi Fukuhara, and Prof. George Matsumura for their helpful discussion in this research.

Funding

This study was supported in part by JSPS KAKENHI Grant numbers JP17K09736, JP20K08616, JP23K07704, and by Japan Agency for Medical Research and Development (18gm5810019h9903).

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Authors and Affiliations

  1. Department of Anatomy, Kyorin University School of Medicine, Mitaka, Japan

    Satoyuki Ogino, Kei Yoshikawa, Kaori Mikami & Miki Nagase

  2. Department of Trauma and Critical Care Medicine, Kyorin University School of Medicine, Mitaka, Japan

    Satoyuki Ogino & Kei Yoshikawa

  3. Kunitachi Aoyagien Tachikawa Geriatric Health Services Facility, Tachikawa, Japan

    Takashi Nagase

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Correspondence to Miki Nagase.

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Esaxerenone was provided by Daiichi Sankyo Co., LTD., Tokyo, Japan.

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Ogino, S., Yoshikawa, K., Nagase, T. et al. Roles of the mechanosensitive ion channel Piezo1 in the renal podocyte injury of experimental hypertensive nephropathy. Hypertens Res 47, 747–759 (2024). https://doi.org/10.1038/s41440-023-01536-z

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