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Podocyte-specific deletion of mechanochannel Piezo1 exacerbates proteinuria and podocyte injury in mouse hypertensive nephropathy

Hypertension Research (2025)Cite this article

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Abstract

Piezo1 is a mechanosensitive ion channel that mediates a broad range of biological and pathological phenomena in living organisms, including hypertension and hypertensive nephropathy. We previously reported the upregulation of Piezo1 in the glomerular podocytes of hypertensive nephropathy mice in vivo and a mechanical stretch-induced podocyte injury cascade via Piezo1 and Rac1 in vitro, suggesting the pathogenic involvement of Piezo1. However, recent reports on podocyte-specific Piezo1 knockout mice with various podocyte injury models other than hypertension have yielded inconsistent results, indicating pathogenic and anti-pathogenic roles of Piezo1. In this study, we generated podocyte-specific Piezo1 knockout mice and examined their podocyte phenotypes under normotensive and hypertensive conditions induced by angiotensin II and a high-salt diet. Podocyte-specific Piezo1 knockout mice did not spontaneously develop podocyte injury. Angiotensin II infusion and a high-salt diet for 14 days caused hypertension, but not significant podocyte injury and proteinuria in the littermate control mice, which were strengthened by podocyte-specific Piezo1 deletion. Through comprehensive transcriptome analysis of the glomeruli of wild-type and podocyte-specific Piezo1 knockout mice, we found altered expression of several genes, including Rhpn1 encoding Rho GTPase binding protein Rhophilin1. Podocyte injury in hypertensive podocyte-specific Piezo1 knockout mice was inhibited by the angiotensin II receptor blocker losartan, the anti-hypertensive drug hydralazine, and partially ameliorated by the Rho kinase inhibitor fasudil, suggesting that podocyte injury in the knockout mice may be mediated by Rhophilin1 and/or Rho signaling downstream of Piezo1. Findings related to the hypertensive podocyte injury model support the possible anti-pathogenic protective roles of Piezo1.

We created podocyte-specific Piezo1 KO mice, and hypertension was induced by angiotensin II and a high-salt diet. Hypertension-evoked proteinuria and podocyte injury were exaggerated in the KO mice. They were ameliorated by anti-hypertensive drugs and Rho kinase inhibitor, suggesting protective roles of Piezo1 and involvement of RhoA signaling.

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References

  1. Mann N, Sun H, Majmundar AJ. Mechanisms of podocyte injury in genetic kidney disease. Pediatr Nephrol. 2025;40:1523–38.

    Article  PubMed  Google Scholar 

  2. Dworkin LD, Hostetter TH, Rennke HG, Brenner BM. Hemodynamic basis for glomerular injury in rats with desoxycorticosterone-salt hypertension. J Clin Invest. 1984;73:1448–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Anderson S, Meyer TW, Rennke HG, Brenner BM. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1985;76:612–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kimura G, Brenner BM The renal basis for salt sensitivity in hypertension. In: Laragh JH, Brenner BM (eds). Hypertension, pathophysiology, diagnosis, and management. 2nd ed. Raven Press: New York, NY, USA, 1995, Vol 1. 1569-88.

  5. Nagase M, Shibata S, Yoshida S, Nagase T, Gotoda T, Fujita T. Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension. 2006;47:1084–93.

    Article  CAS  PubMed  Google Scholar 

  6. Nagase M, Matsui H, Shibata S, Gotoda T, Fujita T. Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. Hypertension. 2007;50:877–83.

    Article  CAS  PubMed  Google Scholar 

  7. Nagase M, Fujita T. Mineralocorticoid receptor activation in obesity hypertension. Hypertens Res. 2009;32:649–57.

    Article  CAS  PubMed  Google Scholar 

  8. Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37:739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308:1801–4.

    Article  CAS  PubMed  Google Scholar 

  10. Endlich K, Kliewe F, Endlich N. Stressed podocytes-mechanical forces, sensors, signaling and response. Pflug Arch. 2017;469:937–49.

    Article  CAS  Google Scholar 

  11. Reynolds PA. The mechanobiology of kidney podocytes in health and disease. Clin Sci. 2020;134:1245–53.

    Article  CAS  Google Scholar 

  12. Haydak J, Azeloglu EU. Role of biophysics and mechanobiology in podocyte physiology. Nat Rev Nephrol. 2024;20:371–85.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Huber TB, Schermer B, Müller RU, Höhne M, Bartram M, Calixto A, et al. Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci USA. 2006;103:17079–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Forst AL, Olteanu VS, Mollet G, Wlodkowski T, Schaefer F, Dietrich A, et al. Podocyte purinergic P2X4 channels are mechanotransducers that mediate cytoskeletal disorganization. J Am Soc Nephrol. 2016;27:848–62.

    Article  CAS  PubMed  Google Scholar 

  15. Tu YC, Shu HP, Sun LL, Liao QQ, Feng L, Ren M, et al. The physiopathologic roles of calcium signaling in podocytes. Front Biosci (Landmark Ed). 2023;28:240, https://doi.org/10.31083/j.fbl2810240.

    Article  CAS  PubMed  Google Scholar 

  16. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010;330:55–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Earley S, Santana LF, Lederer WJ. The physiological sensor channels TRP and piezo: Nobel Prize in Physiology or Medicine 2021. Physiol Rev. 2022;102:1153–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang J, Zhang K, Du R, Liu W, Zhang H, Tian T, et al. The Janus-faced role of Piezo1 in cardiovascular health under mechanical stimulation. Genes Dis. 2023;10:1956–68.

    Article  CAS  PubMed  Google Scholar 

  19. Coste B, Delmas P. PIEZO ion channels in cardiovascular functions and diseases. Circ Res. 2024;134:572–91.

    Article  CAS  PubMed  Google Scholar 

  20. Nagase T, Nagase M. Piezo ion channels: long-sought-after mechanosensors mediating hypertension and hypertensive nephropathy. Hypertens Res. 2024;47:2786–99.

    Article  PubMed  Google Scholar 

  21. Mochida Y, Ochiai K, Nagase T, Nonomura K, Akimoto Y, Fukuhara H, et al. Piezo2 expression and its alteration by mechanical forces in mouse mesangial cells and renin-producing cells. Sci Rep. 2022;12:4197, https://doi.org/10.1038/s41598-022-07987-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ochiai K, Mochida Y, Nagase T, Fukuhara H, Yamaguchi Y, Nagase M. Upregulation of Piezo2 in the mesangial, renin, and perivascular mesenchymal cells of the kidney of Dahl salt-sensitive hypertensive rats and its reversal by esaxerenone. Hypertens Res. 2023;46:1234–46.

    Article  CAS  PubMed  Google Scholar 

  23. Oba R, Ueno H, Oishi A, Nagahama K, Kanzaki G, Tsuboi N, et al. Upregulation of Piezo2 and increased extracellular matrix protein in diabetic kidney disease mice. Hypertens Res. 2025;48:1514–28.

    Article  CAS  PubMed  Google Scholar 

  24. Ogino S, Yoshikawa K, Nagase T, Mikami K, Nagase M. Roles of the mechanosensitive ion channel Piezo1 in the renal podocyte injury of experimental hypertensive nephropathy. Hypertens Res. 2024;47:747–59.

    Article  CAS  PubMed  Google Scholar 

  25. Fu R, Wang W, Huo Y, Li L, Chen R, Lin Z, et al. The mechanosensitive ion channel Piezo1 contributes to podocyte cytoskeleton remodeling and development of proteinuria in lupus nephritis. Kidney Int. 2024;106:625–39.

    Article  CAS  PubMed  Google Scholar 

  26. Li W, Zhang Z, Peng Z, Hu H, Cui X, Zhu Z, et al. Piezo1-mediated calcium signaling and podocyte injury in diabetic kidney disease. J Am Soc Nephrol. 2025;36:1310–26.

    Article  PubMed  Google Scholar 

  27. Melica ME, Antonelli G, Semeraro R, La Regina G, Dafichi T, Fantini C, et al. Piezo1, F-actin remodeling, and podocyte survival and regeneration. J Am Soc Nephrol. e-pub ahead of print 2025/04/02; https://doi.org/10.1681/asn.0000000697.

  28. Albarrán-Juárez J, Iring A, Wang S, Joseph S, Grimm M, Strilic B, et al. Piezo1 and G(q)/G(11) promote endothelial inflammation depending on flow pattern and integrin activation. J Exp Med. 2018;215:2655–72.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cahalan SM, Lukacs V, Ranade SS, Chien S, Bandell M, Patapoutian A. Piezo1 links mechanical forces to red blood cell volume. eLife 2015;4:e07370, https://doi.org/10.7554/eLife.07370.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Asano T, Niimura F, Pastan I, Fogo AB, Ichikawa I, Matsusaka T. Permanent genetic tagging of podocytes: fate of injured podocytes in a mouse model of glomerular sclerosis. J Am Soc Nephrol. 2005;16:2257–62.

    Article  CAS  PubMed  Google Scholar 

  31. Kasahara M, Mukoyama M, Sugawara A, Makino H, Suganami T, Ogawa Y, et al. Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol. 2000;11:1691–701.

    Article  CAS  PubMed  Google Scholar 

  32. Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–6.

    Article  CAS  PubMed  Google Scholar 

  33. Chung JJ, Goldstein L, Chen YJ, Lee J, Webster JD, Roose-Girma M, et al. Single-cell transcriptome profiling of the kidney glomerulus identifies key cell types and reactions to injury. J Am Soc Nephrol. 2020;31:2341–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lal MA, Andersson AC, Katayama K, Xiao Z, Nukui M, Hultenby K, et al. Rhophilin-1 is a key regulator of the podocyte cytoskeleton and is essential for glomerular filtration. J Am Soc Nephrol. 2015;26:647–62.

    Article  CAS  PubMed  Google Scholar 

  35. Greiten JK, Kliewe F, Schnarre A, Artelt N, Schröder S, Rogge H, et al. The role of filamins in mechanically stressed podocytes. FASEB J. 2021;35:e21560, https://doi.org/10.1096/fj.202001179RR.

    Article  CAS  PubMed  Google Scholar 

  36. Kliewe F, Kaling S, Lötzsch H, Artelt N, Schindler M, Rogge H, et al. Fibronectin is up-regulated in podocytes by mechanical stress. FASEB J. 2019;33:14450–60.

    Article  CAS  PubMed  Google Scholar 

  37. Kawachi H, Fukusumi Y. New insight into podocyte slit diaphragm, a therapeutic target of proteinuria. Clin Exp Nephrol. 2020;24:193–204.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Dalghi MG, Clayton DR, Ruiz WG, Al-Bataineh MM, Satlin LM, Kleyman TR, et al. Expression and distribution of PIEZO1 in the mouse urinary tract. Am J Physiol Ren Physiol. 2019;317:F303–21.

    Article  CAS  Google Scholar 

  39. Zhao Y, Duan J, Han ID, van de Leemput J, Ray PE, Han Z. Piezo, nephrocyte function, and slit diaphragm maintenance in Drosophila. J Am Soc Nephrol. 2025;36:393–405.

    Article  PubMed  Google Scholar 

  40. Schulz K, Hazelton-Cavill P, Alornyo KK, Edenhofer I, Lindenmeyer M, Lohr C, et al. Piezo activity levels need to be tightly regulated to maintain normal morphology and function in pericardial nephrocytes. Sci Rep. 2024;14:28254, https://doi.org/10.1038/s41598-024-79352-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, et al. Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science. 1996;271:645–8.

    Article  CAS  PubMed  Google Scholar 

  42. Jin YJ, Chennupati R, Li R, Liang G, Wang S, Iring A, et al. Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation. J Clin Invest. 2021;131:e145734, https://doi.org/10.1172/JCI145734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to Prof. Ardem Patapoutian for his kind gift of the Piezo1fl/fl mice, to Prof. Hidetake Kurihara for providing the rat podocyte cell line, and to Prof. Yoshihiro Akimoto and Prof. Akihiko Kudo for their help with electron microscopy.

Funding

This work was supported in part by JSPS KAKENHI Grant Numbers JP17K09736, JP20K08616, JP23K07704, by Japan Agency for Medical Research and Development (18gm5810019h9903), and by the Salt Science Research Foundation, No.2329.

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Authors and Affiliations

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

    Kaori Mikami, Hisaki Kishino & Miki Nagase

  2. Kunitachi Aoyagien Tachikawa Geriatric Health Services Facility, Tachikawa, Tokyo, Japan

    Takashi Nagase

  3. Institute of Science Tokyo, School of Life Science and Technology, Yokohama, Kanagawa, Japan

    Nobuhiro Nakamura

  4. Department of Physiology, Iwate Medical University, Shiwa-gun, Iwate, Japan

    Yoshiro Suzuki

  5. Department of Urology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

    Hiroshi Fukuhara

  6. Department of Basic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

    Taiji Matsusaka

  7. Institute for Life and Medical Sciences, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan

    Keiko Nonomura

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Mikami, K., Nagase, T., Kishino, H. et al. Podocyte-specific deletion of mechanochannel Piezo1 exacerbates proteinuria and podocyte injury in mouse hypertensive nephropathy. Hypertens Res (2025). https://doi.org/10.1038/s41440-025-02383-w

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