Department of Internal Medicine, The University of Utah, Salt Lake City, UT (R.L., K.T.Y., F.W., H.Z., T.Y.).
Research Service, Veterans Affairs Medical Center, Salt Lake City, UT (R.L., F.W., H.Z., T.Y.).
Hypertension. 2024 Oct;81(10):2152-2161. doi: 10.1161/HYPERTENSIONAHA.123.21740. Epub 2024 Aug 22.
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.
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.
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.
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.
尽管肾脏疾病中肾内肾素-血管紧张素系统（RAS）的概念在文献中已有详细描述，但在没有系统 RAS 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。本研究使用新型的集合管（CD）特异性缺失（前）肾素受体（PRR）或肾素的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脏损伤的确切贡献。
我们研究了 CD 特异性缺失 PRR、CD 特异性缺失肾素和 S1P（位点 1 蛋白酶）抑制剂 PF429242 治疗对单侧输尿管梗阻小鼠模型中肾脏纤维化和炎症以及肾内 RAS 指标的影响。
单侧输尿管梗阻 3 天后，弗洛xed 小鼠梗阻肾脏的肾髓质肾素含量、活性和 mRNA 表达以及 Ang（血管紧张素）II 含量等肾内 RAS 指标均增加。CD 特异性缺失 PRR、CD 特异性缺失肾素和 PF429242 治疗可逆转该效应，同时伴有一致的肾脏纤维化和炎症改善。另一方面，单侧输尿管梗阻对肾皮质肾素水平没有影响，无论基因型如何。通过 S1P 的药理学抑制（可溶性 PRR 生成的关键蛋白酶）得到了类似的结果。
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，因此也是梗阻诱导的肾脏炎症和纤维化的关键决定因素。
