Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah.
Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F941-F953. doi: 10.1152/ajprenal.00197.2020. Epub 2020 Aug 31.
Tubulointerstitial fibrosis has been regarded as a critical event in the pathogenesis of chronic kidney disease. The soluble form of (pro)renin receptor (sPRR), generated by site-1 protease (S1P) cleavage of full-length PRR, can be detected in biological fluid and elevated under certain pathological conditions. The present study was designed to evaluate the potential role of sPRR in the regulation of the fibrotic response in a cultured human renal proximal tubular cell line (HK-2 cells) in the setting of transforming growth factor (TGF)-β or sPRR-His treatment. The TGF-β-induced fibrotic response of HK-2 cells was indicated by upregulation of fibronectin (FN) expression; meanwhile, TGF-β could also induce the generation of sPRR, due to enhanced cleavage of full-length PRR. To explore the role of sPRR in the fibrotic response of HK-2 cells, we blocked the production of sPRR with a the S1P inhibitor PF429242 and found that PF429242 remarkably suppressed TGF-β-induced sPRR generation and FN expression in HK-2 cells. Administration of sPRR-His restored the PF429242-attenuated FN expression in HK-2 cells, indicating that sPRR could promote the TGF-β-induced fibrotic response. Furthermore, sPRR-His alone also increased the abundance of FN in HK-2 cells. These data suggested that sPRR was sufficient and necessary for the TGF-β-induced fibrotic response of HK-2 cells. Mechanistically, sPRR activated the AKT and β-catenin pathway in HK-2 cells, and blockade of the AKT or β-catenin pathway significantly abrogated sPRR-induced FN and Snail expression. Taking together, sPRR promoted the fibrotic response of HK-2 cells by activating Akt/β-catenin/Snail signaling, and it may serve as a potential therapeutic target in renal fibrosis.
肾小管间质纤维化已被认为是慢性肾脏病发病机制中的一个关键事件。（前）肾素受体（PRR）的可溶性形式（sPRR）可通过全长 PRR 的位点 1 蛋白酶（S1P）切割产生，可在生物体液中检测到，并在某些病理条件下升高。本研究旨在评估 sPRR 在 TGF-β或 sPRR-His 处理的培养人近端肾小管细胞系（HK-2 细胞）中调节纤维化反应中的潜在作用。TGF-β诱导的 HK-2 细胞纤维化反应表现为纤连蛋白（FN）表达上调；同时，TGF-β还可以通过增强全长 PRR 的切割来诱导 sPRR 的产生。为了探讨 sPRR 在 HK-2 细胞纤维化反应中的作用，我们用 S1P 抑制剂 PF429242 阻断 sPRR 的产生，发现 PF429242 可显著抑制 TGF-β诱导的 sPRR 生成和 FN 表达。给予 sPRR-His 可恢复 PF429242 减弱的 HK-2 细胞 FN 表达，表明 sPRR 可促进 TGF-β诱导的纤维化反应。此外，sPRR-His 本身也增加了 HK-2 细胞中 FN 的丰度。这些数据表明 sPRR 足以且有必要促进 HK-2 细胞的 TGF-β诱导的纤维化反应。在机制上，sPRR 激活了 HK-2 细胞中的 AKT 和 β-catenin 通路，而 AKT 或 β-catenin 通路的阻断可显著抑制 sPRR 诱导的 FN 和 Snail 表达。综上所述，sPRR 通过激活 Akt/β-catenin/Snail 信号通路促进 HK-2 细胞的纤维化反应，它可能是肾脏纤维化的潜在治疗靶点。
