BACKGROUND Although the concept of the intrarenal renin-angiotensin system (RAS) in renal disease is well-described in the literature, the precise pathogenic role and mechanism of this local system have not been directly assessed in the absence of confounding influence from the systemic RAS. The present study used novel mouse models of collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) or renin together with pharmacological inhibition of soluble PRR production to unravel the precise contribution of the intrarenal RAS to renal injury induced by unilateral ureteral obstruction. METHODS We examined the impact of CD-specific deletion of PRR, CD-specific deletion of renin, and S1P (site-1 protease) inhibitor PF429242 treatment on renal fibrosis and inflammation and the indices of the intrarenal RAS in a mouse model of unilateral ureteral obstruction. RESULTS After 3 days of unilateral ureteral obstruction, the indices of the intrarenal RAS including the renal medullary renin content, activity and mRNA expression, and Ang (angiotensin) II content in obstructed kidneys of floxed mice were all increased. That effect was reversed with CD-specific deletion of PRR, CD-specific deletion of renin, and PF429242 treatment, accompanied by consistent improvement in renal fibrosis and inflammation. On the other hand, renal cortical renin levels were unaffected by unilateral ureteral obstruction, irrespective of the genotype. Similar results were obtained via pharmacological inhibition of S1P, the key protease for the generation of soluble PRR. CONCLUSIONS Our results reveal that PRR-dependent/soluble PRR-dependent activation of CD renin represents a key determinant of the intrarenal RAS and, thus, obstruction-induced renal inflammation and fibrosis.

中文翻译：

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集合管前体 （肾素） 受体通过激活肾内 RAS 导致单侧输尿管梗阻诱导的肾损伤。


背景 尽管文献中肾内肾素-血管紧张素系统 （RAS） 的概念在文献中得到了很好的描述，但在没有系统性 RAS 的混杂影响的情况下，尚未直接评估该局部系统的确切致病作用和机制。本研究使用集合管 （CD） 特异性缺失 （pro）肾素受体 （PRR） 或肾素的新型小鼠模型以及可溶性 PRR 产生的药理学抑制来揭示肾内 RAS 对单侧输尿管梗阻诱导的肾损伤的确切贡献。方法 我们检查了 CD 特异性 PRR 缺失、CD 特异性肾素缺失和 S1P （site-1 protease） 抑制剂PF429242治疗对肾纤维化和炎症的影响以及单侧输尿管梗阻小鼠模型中肾内 RAS 的指数。结果 单侧输尿管梗阻 3 d 后，絮凝小鼠肾内 RAS 指标包括肾髓样肾素含量、活性和 mRNA 表达，以及梗阻肾中血管紧张素 II 含量均升高。这种效果通过 PRR 的 CD 特异性缺失、肾素的 CD 特异性缺失和 PF429242 治疗而逆转，并伴有肾纤维化和炎症的持续改善。另一方面，肾皮质肾素水平不受单侧输尿管梗阻的影响，与基因型无关。通过药理学抑制 S1P（产生可溶性 PRR 的关键蛋白酶）获得了类似的结果。结论我们的结果表明，CD 肾素的 PRR 依赖性/可溶性 PRR 依赖性激活是肾内 RAS 的关键决定因素，因此是梗阻诱导的肾脏炎症和纤维化。