Tubulointerstitial fibrosis has been regarded as a critical event in the pathogenesis of chronic kidney disease (CKD). Soluble form of PRR (sPRR), generated by site-1 protease (S1P) cleavage of full-length PRR, is detected in biological fluid and elevated under certain pathological conditions. The present study was designed to evaluate the potential role of sPRR in regulation of fibrotic response in cultured human renal proximal tubular cell line human kidney 2 (HK-2) cells, in the setting of TGF-β or sPRR-His treatment. TGF-β induced fibrotic response of HK-2 cells was indicated by the upregulation of fibronectin (FN) expression, meanwhile, TGF-β could also induce the generation of sPRR, due to enhanced cleavage of fPRR. To explore the role of sPRR in fibrotic response of HK-2 cells, we blocked the production of sPRR with a 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 PF429242 attenuated FN expression in HK-2 cells, indicating that sPRR could promote 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 TGF-ß-induced fibrotic response of HK-2 cells. Mechanistically, sPRR activated the AKT and β-catenin pathway in HK-2 cells, and blockade of 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.

中文翻译：

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可溶性（原）肾素受体通过Akt /β-catenin/ Snail信号通路在体外促进肾近端小管上皮细胞的纤维化反应。

肾小管间质纤维化已被认为是慢性肾脏病（CKD）发病机制中的关键事件。在生物流体中检测到可溶形式的PRR（sPRR），该酶由位点1蛋白酶（S1P）裂解全长PRR产生，并在某些病理条件下升高。本研究旨在评估在TGF-β或sPRR-His的治疗中sPRR在调节培养的人肾近端肾小管细胞系人肾2（HK-2）细胞纤维化反应中的潜在作用。TGF-β诱导的HK-2细胞纤维化反应通过纤连蛋白（FN）表达的上调来表明，同时，由于fPRR的切割增强，TGF-β还可以诱导sPRR的产生。要探索sPRR在HK-2细胞纤维化反应中的作用，我们用S1P抑制剂PF429242阻断了sPRR的产生，发现PF429242显着抑制了TGF-β诱导的HK-2细胞中sPRR的产生和FN的表达。施用sPRR-His可恢复PF429242在HK-2细胞中的FN表达减弱，表明sPRR可促进TGF-β诱导的纤维化反应。此外，仅sPRR-His还可增加HK-2细胞中FN的含量。这些数据表明，sPRR对于TGF-β诱导的HK-2细胞纤维化反应是足够且必要的。从机制上讲，sPRR激活了HK-2细胞中的AKT和β-catenin途径，而AKT或β-catenin途径的阻断则显着消除了sPRR诱导的FN和Snail表达。综上所述，sPRR通过激活Akt /β-catenin/ Snail信号传导促进HK-2细胞的纤维化反应，