GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy

• Published in: Acta pharmacologica Sinica Vol. 44; no. 6; pp. 1206 - 1216
• Main Authors: Wu, Ji-chao, Wang, Xiao-jie, Zhu, Jing-han, Huang, Xue-ying, Liu, Min, Qiao, Zhe, Zhang, Yan, Sun, Yu, Wang, Zi-ying, Zhan, Peng, Zhang, Tao, Hu, Hui-li, Liu, Hong, Tang, Wei, Yi, Fan
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.06.2023; Nature Publishing Group
• Subjects: Acetic acid; Animals; Biomedical and Life Sciences; Biomedicine; Biopsy; Blood pressure; Clathrin; Cytoskeleton; Desoxycorticosterone Acetate - adverse effects; End-stage renal disease; Endocytosis; Fibrosis; G protein-coupled receptors; Hypertension; Hypertension - drug therapy; Hypertension, Renal - drug therapy; Hypertension, Renal - metabolism; Hypertension, Renal - pathology; Immunology; Internal Medicine; Kidney - pathology; Kidney diseases; Medical Microbiology; Mice; Nephropathy; Pharmacology/Toxicology; Renal tubules; RhoA protein; Smad protein; Therapeutic targets; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Vaccine; hypertensive nephropathy; GPR97; TGF-β; endocytosis; tubulointerstitial fibrosis; Smad
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-022-01041-y

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.