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 Pro（肾素）受体通过激活肾内 RAS 导致单侧输尿管梗阻引起的肾脏损伤。


背景 尽管肾病中肾内肾素-血管紧张素系统 (RAS) 的概念在文献中有详细描述，但在没有全身 RAS 的混杂影响的情况下，该局部系统的精确致病作用和机制尚未得到直接评估。 。本研究使用肾素（原）受体（PRR）或肾素的集合管（CD）特异性缺失的新型小鼠模型，以及可溶性 PRR 产生的药理学抑制，以揭示肾内 RAS 对单侧肾损伤的精确贡献输尿管梗阻。方法 我们在单侧输尿管小鼠模型中研究了 CD 特异性删除 PRR、CD 特异性删除肾素和 S1P（位点 1 蛋白酶）抑制剂 PF429242 治疗对肾纤维化和炎症以及肾内 RAS 指数的影响。梗阻。结果单侧输尿管梗阻3 d后，floxed小鼠肾内RAS指标，包括肾髓质肾素含量、活性和mRNA表达量，以及梗阻肾中Ang（血管紧张素）II含量均升高。 CD 特异性删除 PRR、CD 特异性删除肾素和 PF429242 治疗可逆转这种效应，同时肾纤维化和炎症得到持续改善。另一方面，无论基因型如何，肾皮质肾素水平不受单侧输尿管梗阻的影响。通过药理抑制 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，因此也是梗阻性肾脏炎症和纤维化的关键决定因素。