The function and regulation of intrarenal aldosterone synthase in ischemia-induced hypertension and renal injury

Va Salt Lake City Healthcare System, Salt Lake City UT

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Abstract

Aldosterone (Aldo) as a key component of the renin-angiotensin-aldosterone system (RAAS) plays a key role in pathogenesis of hypertension and kidney disease in addition to its role in primary aldosteronism. Importance of this pathway is highlighted by clinical use of various types of mineralocorticoid receptor (MR) antagonists, particularly the phase 2 clinical trial of CYP11B2 inhibitor baxdrostat for treatment of resistant hypertension (Freeman et al. N Engl J Med. 2023). Apart from adrenal origin, extra-adrenal production of Aldo participates in many physio-pathological processes in multiple organs including the kidney. Longer than a decade ago, a small number of studies reported intrarenal Aldo production and expression of CYP11B2 implicated in pathogenesis of diabetic kidney disease. In preliminary studies, we for the first time generated a novel mouse model of renal tubule-specific deletion of CYP11B2 (RT CYP11B2 KO) and observed an intriguing phenotype during 2-kidney, 1-clip (2K1C)-induced renovascular hypertension and renal injury, providing genetic evidence favoring a pathogenetic role of intrarenal CYP11B2 in this model. We provided further evidence that intrarenal CYP11B2 was under the control of soluble (pro)renin receptor (sPRR) derived from site-1 protease (S1P)-dependent cleavage of PRR in the collecting duct (CD). Therefore, we hypothesize that during renal hypoxia, S1P cleaves PRR in the CD to release sPRR that stimulates expression of CYP11B2 and production of Aldo, ultimately resulting in elevation of blood pressure and kidney injury. To test this hypothesis, we will comprehensively examine the phenotype of RT CYP11B2 KO mice during 2K1C-indued hypertension as well as acute ischemia reperfusion injury (IRI) and its transition to chronic kidney disease (CKD). Secondly, we will test the effect of CD PRR KO on intrarenal Aldo biosynthesis and further to examine the cellular mechanism of sPRR regulation of CYP11B2 expression in cultured renal epithelial cells during hypoxia. Overall, the current proposal is expected to offer novel insights into the potential role of intrarenal Aldo generation in ischemia-induced hypertension and renal injury.