Fu Ziwei, Zou Chang-Jiang, Kimball Alex, Yang Tianxin
bioRxiv. 2025 Aug 27:2025.08.24.671658. doi: 10.1101/2025.08.24.671658.
The past few years have witnessed a significant advancement in aldosterone (Aldo)-targeted therapies for the management of treatment-resistant hypertension and chronic kidney disease, which often exist in tandem. While Aldo is believed to predominantly originate from the adrenal glands, this study provides evidence to support the involvement of intrarenal Aldo biosynthesis in the pathogenesis of ischemic nephropathy and hypertension in a two-kidney, one-clip (2K1C) model.
We generated inducible renal tubule-specific deletion of C11B2 (RT C11B2 KO) and characterized the phenotype during the 2K1C procedure. We investigated the underlying mechanisms involving the use of mice with collecting duct-specific (pro)renin receptor (CD PRR KO) or renin (CD renin KO).
RT C11B2 KO induced a partial blockade of the hypertensive response but a much greater improvement in renal fibrosis and inflammation four weeks post-2K1C. This phenotype was associated with an effective blockade of intrarenal generation of Aldo contrasting to unchanged circulating Aldo concentrations. Furthermore, clipping-induced acute kidney injury was also attenuated 24 hours post-2K1C, at which point blood pressure (BP) did not increase. Similarly, sodium nitroprusside effectively lowered BP in C57BL/6j/2K1C mice but failed to improve renal injury. Additionally, we identified CD) PRR and renin as key upstream regulators of intrarenal Aldo biosynthesis following the 2K1C procedure.
Together, these results support the idea that CD PRR/renin-dependent generation of intrarenal Aldo may play a primary role in the pathogenesis of ischemic nephropathy and a secondary role in hypertension development during renovascular constriction. Therefore, targeting intrarenal Aldo biosynthesis may represent a more effective and safer intervention than existing Aldo-targeted therapy to manage ischemic nephropathy as well as hypertension.
在过去几年中，用于治疗顽固性高血压和慢性肾病（这两种疾病常常同时存在）的醛固酮（Aldo）靶向疗法取得了重大进展。虽然人们认为醛固酮主要来源于肾上腺，但本研究提供了证据，支持在二肾一夹（2K1C）模型中，肾内醛固酮生物合成参与缺血性肾病和高血压的发病机制。
我们构建了可诱导的肾小管特异性C11B2缺失（RT C11B2 KO）模型，并在2K1C过程中对其表型进行了表征。我们使用集合管特异性（前）肾素受体缺失小鼠（CD PRR KO）或肾素缺失小鼠（CD renin KO）来研究潜在机制。
RT C11B2 KO在2K1C术后四周诱导了高血压反应的部分阻断，但在肾纤维化和炎症方面有更大改善。这种表型与肾内醛固酮生成的有效阻断相关，而循环醛固酮浓度未改变。此外，夹闭诱导的急性肾损伤在2K1C术后24小时也有所减轻，此时血压（BP）并未升高。同样，硝普钠可有效降低C57BL/6j/2K1C小鼠的血压，但未能改善肾损伤。此外，我们确定CD PRR和肾素是2K1C术后肾内醛固酮生物合成的关键上游调节因子。
总之，这些结果支持以下观点，即CD PRR/肾素依赖性肾内醛固酮生成可能在缺血性肾病的发病机制中起主要作用，而在肾血管收缩期间高血压发展中起次要作用。因此，针对肾内醛固酮生物合成进行靶向治疗可能比现有的醛固酮靶向治疗更有效、更安全，可用于管理缺血性肾病和高血压。
