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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

Hypertension Research volume 46, pages 1234–1246 (2023)Cite this article

Abstract

The recent discovery of mechanosensitive ion channels has promoted mechanobiological research in the field of hypertension and nephrology. We previously reported Piezo2 expression in mouse mesangial and juxtaglomerular renin-producing cells, and its modulation by dehydration. This study aimed to investigate how Piezo2 expression is altered in hypertensive nephropathy. The effects of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, were also analyzed. Four-week-old Dahl salt-sensitive rats were randomly assigned to three groups: rats fed a 0.3% NaCl diet (DSN), rats fed a high 8% NaCl diet (DSH), and rats fed a high salt diet supplemented with esaxerenone (DSH + E). After six weeks, DSH rats developed hypertension, albuminuria, glomerular and vascular injuries, and perivascular fibrosis. Esaxerenone effectively decreased blood pressure and ameliorated renal damage. In DSN rats, Piezo2 was expressed in Pdgfrb-positive mesangial and Ren1-positive cells. Piezo2 expression in these cells was enhanced in DSH rats. Moreover, Piezo2-positive cells accumulated in the adventitial layer of intrarenal small arteries and arterioles in DSH rats. These cells were positive for Pdgfrb, Col1a1, and Col3a1, but negative for Acta2 (αSMA), indicating that they were perivascular mesenchymal cells different from myofibroblasts. Piezo2 upregulation was reversed by esaxerenone treatment. Furthermore, Piezo2 inhibition by siRNA in the cultured mesangial cells resulted in upregulation of Tgfb1 expression. Cyclic stretch also upregulated Tgfb1 in both transfections of control siRNA and Piezo2 siRNA. Our findings suggest that Piezo2 may have a contributory role in modulating the pathogenesis of hypertensive nephrosclerosis and have also highlighted the therapeutic effects of esaxerenone on salt-induced hypertensive nephropathy.

Mechanochannel Piezo2 is known to be expressed in the mouse mesangial cells and juxtaglomerular renin-producing cells, and this was confirmed in normotensive Dahl-S rats. In salt-induced hypertensive Dahl-S rats, Piezo2 upregulation was observed in the mesangial cells, renin cells, and notably, perivascular mesenchymal cells, suggesting its involvement in kidney fibrosis.

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References

  1. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N. Engl J Med. 1988;318:1657–66.

    Article  CAS  PubMed  Google Scholar 

  2. Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet. 1997;350:1734–7.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. 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 

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

  6. 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 

  7. Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121:3233–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KR, Xiao L, et al. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest. 2016;126:50–67.

    Article  PubMed  Google Scholar 

  9. 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 

  10. Szczot M, Nickolls AR, Lam RM, Chesler AT. The form and function of PIEZO2. Annu Rev Biochem. 2021;90:507–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, et al. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science. 2018;362:464–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  13. Arai K, Tsuruoka H, Homma T. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J Pharm. 2015;769:266–73.

    Article  CAS  Google Scholar 

  14. Li L, Guan Y, Kobori H, Morishita A, Kobara H, Masaki T, et al. Effects of the novel nonsteroidal mineralocorticoid receptor blocker, esaxerenone (CS-3150), on blood pressure and urinary angiotensinogen in low-renin Dahl salt-sensitive hypertensive rats. Hypertens Res. 2019;42:769–78.

    Article  CAS  PubMed  Google Scholar 

  15. Olson JL, Wilson SK, Heptinstall RH. Relation of glomerular injury to preglomerular resistance in experimental hypertension. Kidney Int. 1986;29:849–57.

    Article  CAS  PubMed  Google Scholar 

  16. Hirakata M, Kaname S, Chung UG, Joki N, Hori Y, Noda M, et al. Tyrosine kinase dependent expression of TGF-beta induced by stretch in mesangial cells. Kidney Int. 1997;51:1028–36.

    Article  CAS  PubMed  Google Scholar 

  17. Moon JY, Tanimoto M, Gohda T, Hagiwara S, Yamazaki T, Ohara I, et al. Attenuating effect of angiotensin-(1-7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-A(y)/Ta mice. Am J Physiol Ren Physiol. 2011;300:F1271–82.

    Article  CAS  Google Scholar 

  18. Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol. 2006;17:3438–46.

    Article  CAS  PubMed  Google Scholar 

  19. Shibota M, Nagaoka A, Shino A, Fujita T. Renin-angiotensin system in stroke-prone spontaneously hypertensive rats. Am J Physiol. 1979;236:H409–16.

    CAS  PubMed  Google Scholar 

  20. Yasuda T, Kondo S, Homma T, Harris RC. Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells. J Clin Invest. 1996;98:1991–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao F, Wang DH. Impairment in function and expression of transient receptor potential vanilloid type 4 in Dahl salt-sensitive rats: significance and mechanism. Hypertension. 2010;55:1018–25.

    Article  CAS  PubMed  Google Scholar 

  22. Zhou Y, Castonguay P, Sidhom EH, Clark AR, Dvela-Levitt M, Kim S, et al. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science. 2017;358:1332–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fu Y, Wan P, Zhang J, Li X, Xing J, Zou Y, et al. Targeting mechanosensitive Piezo1 alleviated renal fibrosis through p38MAPK-YAP pathway. Front Cell Dev Biol. 2021;9:741060. https://doi.org/10.3389/fcell.2021.741060.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhao X, Kong Y, Liang B, Xu J, Lin Y, Zhou N, et al. Mechanosensitive Piezo1 channels mediate renal fibrosis. JCI Insight. 2022;7:e152330. https://doi.org/10.1172/jci.insight.152330.

    Article  PubMed  PubMed Central  Google Scholar 

  25. He Y, Deng B, Liu S, Luo S, Ning Y, Pan X, et al. Myeloid Piezo1 deletion protects renal fibrosis by restraining macrophage infiltration and activation. Hypertension. 2022;79:918–31.

    Article  CAS  PubMed  Google Scholar 

  26. Sakai T, Kriz W. The structural relationship between mesangial cells and basement membrane of the renal glomerulus. Anat Embryol (Berl). 1987;176:373–86.

    Article  CAS  PubMed  Google Scholar 

  27. Di Carlo SE, Peduto L. The perivascular origin of pathological fibroblasts. J Clin Invest. 2018;128:54–63.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Minatoguchi S, Saito S, Furuhashi K, Sawa Y, Okazaki M, Shimamura Y, et al. A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts. Sci Rep. 2022;12:5389. https://doi.org/10.1038/s41598-022-09331-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shaw I, Rider S, Mullins J, Hughes J, Péault B. Pericytes in the renal vasculature: roles in health and disease. Nat Rev Nephrol. 2018;14:521–34.

    Article  CAS  PubMed  Google Scholar 

  30. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gerarduzzi C, Di Battista JA. Myofibroblast repair mechanisms post-inflammatory response: a fibrotic perspective. Inflamm Res. 2017;66:451–65.

    Article  CAS  PubMed  Google Scholar 

  32. Schimmel K, Ichimura K, Reddy S, Haddad F, Spiekerkoetter E. Cardiac fibrosis in the pressure overloaded left and right ventricle as a therapeutic target. Front Cardiovasc Med. 2022;9:886553. https://doi.org/10.3389/fcvm.2022.886553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Talbott HE, Mascharak S, Griffin M, Wan DC, Longaker MT. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. 2022;29:1161–80.

    Article  CAS  PubMed  Google Scholar 

  34. Black LM, Lever JM, Agarwal A. Renal inflammation and fibrosis: a double-edged sword. J Histochem Cytochem. 2019;67:663–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell. 2015;16:51–66.

    Article  CAS  PubMed  Google Scholar 

  36. Kuppe C, Ibrahim MM, Kranz J, Zhang X, Ziegler S, Perales-Patón J, et al. Decoding myofibroblast origins in human kidney fibrosis. Nature. 2021;589:281–6.

    Article  CAS  PubMed  Google Scholar 

  37. Weller RO. Vascular pathology in hypertension. Age Ageing. 1979;8:99–103.

    Article  CAS  PubMed  Google Scholar 

  38. Correa-Rotter R, Hostetter TH, Manivel JC, Rosenberg ME. Renin expression in renal ablation. Hypertension. 1992;20:483–90.

    Article  CAS  PubMed  Google Scholar 

  39. Konda R, Orikasa S, Sakai K, Ota S, Kimura N. The distribution of renin containing cells in scarred kidneys. J Urol. 1996;156:1450–4.

    Article  CAS  PubMed  Google Scholar 

  40. Faraggiana T, Venkataseshan VS, Inagami T, Churg J. Immunohistochemical localization of renin in end-stage kidneys. Am J Kidney Dis. 1988;12:194–9.

    Article  CAS  PubMed  Google Scholar 

  41. Kintscher U, Bakris GL, Kolkhof P. Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Br J Pharm. 2022;179:3220–34.

    Article  CAS  Google Scholar 

  42. Tezuka Y, Ito S. The time to reconsider mineralocorticoid receptor blocking strategy: arrival of nonsteroidal mineralocorticoid receptor blockers. Curr Hypertens Rep. 2022;24:215–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Ennis IL, Pérez NG. Cardiac mineralocorticoid receptor and the Na+/H+ exchanger: spilling the beans. Front Cardiovasc Med. 2020;7:614279. https://doi.org/10.3389/fcvm.2020.614279.

    Article  CAS  PubMed  Google Scholar 

  45. Chambers L, Dorrance AM. Regulation of ion channels in the microcirculation by mineralocorticoid receptor activation. Curr Top Membr. 2020;85:151–85.

    Article  CAS  PubMed  Google Scholar 

  46. Cosgun ZC, Sternak M, Fels B, Bar A, Kwiatkowski G, Pacia MZ, et al. Rapid shear stress-dependent ENaC membrane insertion is mediated by the endothelial glycocalyx and the mineralocorticoid receptor. Cell Mol Life Sci. 2022;79:235. https://doi.org/10.1007/s00018-022-04260-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Ms. Kaori Mikami for her technical support.

Funding

This work was supported in part by JSPS KAKENHI Grant Number JP17K09736 and JP20K08616, 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, Tokyo, Japan

    Koji Ochiai, Yuki Mochida & Miki Nagase

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

    Koji Ochiai, Yuki Mochida & Yoshihiro Yamaguchi

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

    Takashi Nagase

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

    Hiroshi Fukuhara

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

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Ochiai, K., Mochida, Y., Nagase, T. et al. 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 46, 1234–1246 (2023). https://doi.org/10.1038/s41440-023-01219-9

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