Role of (pro)renin receptor in cyclosporin A-induced nephropathy.
Role of (pro)renin receptor in cyclosporin A-induced nephropathy.
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肾素（原）受体在环孢菌素 A 诱导的肾病中的作用。
DOI：
10.1152/ajprenal.00332.2021
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Yang,Tianxin
中科院分区：
文献类型：
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作者：
Hu,Jiajia;Tan,Yandan;Chen,Yanting;Mo,Shiqi;Hekking,Brittin;Su,Jiahui;Pu,Min;Lu,Aihua;Du,Yanhua;Symons,JDavid;Yang,Tianxin
钙调磷酸酶抑制剂如环孢菌素A（CsA）已被广泛用于提高实体器官移植后的移植物存活率。然而，CsA的临床应用往往受到其肾毒性的限制。本研究验证了一个假设，即（原）肾素受体（PRR）的激活有助于通过激活肾素-血管紧张素系统（RAS）的CsA诱导的肾病。低盐饮食联合CsA诱导雄性Sprague-Dawley大鼠肾损伤，表现为血浆肌酐和血尿素氮水平升高，肌酐清除率降低，诱导肾脏炎症、细胞凋亡和间质纤维化，尿N-乙酰-β-d-氨基葡萄糖苷酶活性和尿肾损伤分子-1含量升高。在用PRR诱饵抑制剂PRO 20治疗2周后，肾损伤的每个指数都减弱。尽管CsA治疗的肾损伤大鼠显示肾可溶性PRR丰度、血浆sPRR、肾素活性、血管紧张素II和尿总原肾素/肾素含量升高，但PRO 20减弱了RAS激活。暴露于CsA诱导的人肾近端肾小管HK-2细胞的纤连蛋白表达和sPRR的产生，但纤维化反应减弱PRO20和siRNA介导的PRR敲低。这些发现支持了PRR的激活通过激活大鼠RAS而促进CsA诱导的肾病的假设。重要的是，我们提供了强有力的证据的概念，针对PRR提供了一种新的治疗策略，以限制免疫抑制药物的肾毒性作用。新&值得注意的是，本研究报告，第一次，激活的（原）肾素受体驱动的肾素-血管紧张素系统诱导肾损伤环孢素A管理。更重要的是，我们的研究已经确定，与PRO 20的拮抗作用提供了一种新的干预环孢菌素A副作用的管理。
Calcineurin inhibitors such as cyclosporin A (CsA) have been widely used to improve graft survival following solid-organ transplantation. However, the clinical use of CsA is often limited by its nephrotoxicity. The present study tested the hypothesis that activation of the (pro)renin receptor (PRR) contributes to CsA-induced nephropathy by activating the renin-angiotensin system (RAS). Renal injury in male Sprague-Dawley rats was induced by a low-salt diet combined with CsA as evidenced by elevated plasma creatinine and blood urea nitrogen levels, decreased creatinine clearance and induced renal inflammation, apoptosis and interstitial fibrosis, and elevated urinaryN-acetyl-β-d-glucosaminidase activity and urinary kidney injury molecule-1 content. Each index of renal injury was attenuated following 2 wk of treatment with the PRR decoy inhibitor PRO20. Although CsA-treated rats with kidney injury displayed increased renal soluble (s)PRR abundance, plasma sPRR, renin activity, angiotensin II, and heightened urinary total prorenin/renin content, RAS activation was attenuated by PRO20. Exposure of cultured human renal proximal tubular HK-2 cells to CsA induced expression of fibronectin and sPRR production, but the fibrotic response was attenuated by PRO20 and siRNA-mediated PRR knockdown. These findings support the hypothesis that activation of PRR contributes to CsA-induced nephropathy by activating the RAS in rats. Of importance, we provide strong proof of concept that targeting PRR offers a novel therapeutic strategy to limit nephrotoxic effects of immunosuppressant drugs.NEW & NOTEWORTHYThe present study reports, for the first time, that activation of the (pro)renin receptor drives the renin-angiotensin system to induce renal injury during cyclosporin A administration. More importantly, our study has identified that antagonism with PRO20 offers a novel intervention in the management of side effects of cyclosporin A.