Abstract
Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97−/− mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-β signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-β receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-β signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.
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Acknowledgements
This study was supported by the National Key R&D Program of China (2020YFC2005000); the National Natural Science Foundation of China (82090024 to FY, 91949202 to FY, 82270718 to WT, 81970580 to WT, 81800643 to JCW, 82170734 to XJW, 81800645 to ML); and the Shandong Provincial Natural Science Foundation (ZR2019ZD40 to FY, ZR202102240178 to XJW).
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FY, WT and XJW conceived and designed the research. JCW, JHZ, XYH and ZQ performed the research and acquired the data. ML, YZ, YS, PZ, HLH, TZ, HL, and ZYW analyzed and interpreted the data. All authors were involved in drafting and revising the manuscript.
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Wu, Jc., Wang, Xj., Zhu, Jh. et al. GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy. Acta Pharmacol Sin 44, 1206–1216 (2023). https://doi.org/10.1038/s41401-022-01041-y
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DOI: https://doi.org/10.1038/s41401-022-01041-y