GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy

Ji-chao Wu1, Xiao-jie Wang1, Jing-han Zhu1, Xue-ying Huang1, Min Liu1, Zhe Qiao1, Yan Zhang1, Yu Sun1, Zi-ying Wang1, Peng Zhan2, Tao Zhang3, Hui-li Hu4, Hong Liu5, Wei Tang6, Fan Yi1
1 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012 China
2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012 China
3 Department of Biostatistics, School of Public Health, Shandong University, Jinan 250012 China
4 Department of Systems Biomedicine and Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Shandong University, Jinan 250012 China
5 State Key Laboratory of Crystal Materials, Shandong University, Jinan 250012 China
6 Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012 China
Correspondence to: Wei Tang:, Fan Yi:,
DOI: 10.1038/s41401-022-01041-y
Received: 14 October 2022
Accepted: 12 December 2022
Advance online: 12 January 2023


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.
Keywords: hypertensive nephropathy; tubulointerstitial fibrosis; GPR97; TGF-β; Smad; endocytosis

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