(Pro)renin receptor mediates albumin-induced cellular responses: role of site-1 protease-derived soluble (pro)renin receptor in renal epithelial cells
(Pro)renin receptor mediates albumin-induced cellular responses: role of site-1 protease-derived soluble (pro)renin receptor in renal epithelial cells
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DOI：
10.1152/ajpcell.00006.2017
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发表时间：
2017-12-01
影响因子：
5.5
通讯作者：
Yang, Tianxin
中科院分区：
文献类型：
--
作者：
Fang, Hui;Xu, Chuanming;Yang, Tianxin
蛋白尿是慢性肾脏疾病的特征，也是促进疾病进展的致病因素，部分是通过激活肾内肾素血管紧张素系统(RAS)来实现的。肾素受体(PRR)是一种新发现的RAS成分，它与肾素和(PRO)肾素结合，促进血管紧张素I的生成。本研究旨在探讨可溶性PRR(SPRR)在人肾近端小管上皮细胞系HK-2细胞白蛋白超载反应中的作用。20 mg/ml的牛血清白蛋白(BSA)处理24小时可诱导肾素活性和炎症，而PRR诱骗抑制剂Pro20可减轻这两种作用。牛血清白蛋白处理后，由于促进了PRR的切割，中等水平的sPRR增加了五倍以上。令人惊讶的是，这种切割事件不受Furin或去整合素和金属蛋白酶19抑制的影响。通过对一种新的切割酶的筛选，鉴定出了S1P。用PF-429242或siRNA抑制S1P可显著抑制牛血清白蛋白诱导的sPRR的产生、肾素活性和炎症反应。给予一种被称为sPRR-His的重组sPRR可逆转S1P抑制的作用。在高表达PRR的HK-2细胞中，S1P的突变，而不是Furin裂解位点的突变，降低了sPRR水平。综上所述，这些结果表明，PRR通过S1P来源的sPRR介导白蛋白诱导的细胞反应。
Proteinuria is a characteristic of chronic kidney disease and also a causative factor that promotes the disease progression, in part, via activation of the intrarenal reninangiotensin system (RAS). (Pro) renin receptor (PRR), a newly discovered component of the RAS, binds renin and (pro) renin to promote angiotensin I generation. The present study was performed to test the role of soluble PRR (sPRR) in albumin overload-induced responses in cultured human renal proximal tubular cell line human kidney 2 (HK-2) cells. Bovine serum albmuin (BSA) treatment for 24 h at 20 mg/ ml induced renin activity and inflammation, both of which were attenuated by a PRR decoy inhibitor PRO20. BSA treatment induced a more than fivefold increase in medium sPRR due to enhanced cleavage of PRR. Surprisingly, this cleavage event was unaffected by inhibition of furin or a disintegrin and metalloproteinase 19. Screening for a novel cleavage enzyme led to the identification of site-1 protease (S1P). Inhibition of S1P with PF-429242 or siRNA remarkably suppressed BSA-induced sPRR production, renin activity, and inflammatory response. Administration of a recombinant sPRR, termed sPRR-His, reversed the effects of S1P inhibition. In HK-2 cells overexpressing PRR, mutagenesis of the S1P, but not furin cleavage site, reduced sPRR levels. Together, these results suggest that PRR mediates albumin-induced cellular responses through S1P-derived sPRR.