GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy
GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy
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DOI：
10.1038/s41401-022-01041-y
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发表时间：
2023-01
影响因子：
8.2
通讯作者：
Ji-chao Wu;Xiao-jie Wang;Jing-Han Zhu;Xue-Ying Huang;Min Liu;Zhe Qiao;Yan Zhang;Yu Sun;Zi-ying Wang;P. Zhan;Tao Zhang;Hui-Li Hu;Hong Liu;Wei-xue Tang;Fan Yi
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文献类型：
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作者：
Ji-chao Wu;Xiao-jie Wang;Jing-Han Zhu;Xue-Ying Huang;Min Liu;Zhe Qiao;Yan Zhang;Yu Sun;Zi-ying Wang;P. Zhan;Tao Zhang;Hui-Li Hu;Hong Liu;Wei-xue Tang;Fan Yi
高血压肾病(HTN)是终末期肾病(ESRD)的第二大病因。越来越多的证据表明，持续性高血压损伤肾小管上皮细胞，导致肾小管间质纤维化(TIF)，参与HTN的发病机制。G蛋白偶联受体(GPCRs)参与许多重要的病理生理过程，是重要的药物靶点。在这项研究中，我们探讨了高血压相关性TIF的肾内机制，特别是粘附性GPCR亚家族成员GPR97在TIF中的潜在作用。采用醋酸脱氧皮质酮(DOCA)/盐诱导的高血压小鼠模型。我们发现GPR97在高血压小鼠和10例经活检证实的高血压肾损伤患者的肾脏中显著上调，尤其是在肾小管中。GPR97DOCA/盐治疗后−/−小鼠血压显著升高，与野生型小鼠相当，但肾脏损伤和TIF显著改善。在NRK-52E细胞中，我们证明了GPR97的敲除通过干扰小GTP酶RhoA介导的细胞骨架重组抑制了转化生长因子-β信号的激活，从而抑制了笼蛋白介导的转化生长因子-β受体的内吞和随后的Smad激活。总之，这项研究表明GPR97至少部分通过促进转化生长因子-β信号转导而促进高血压相关的TIF，提示GPR97是高血压条件下TIF进展的一个关键的肾内因子，针对GPR97的治疗策略可能改善HTN患者的预后。
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.