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Published on: October 26, 2020
Intrarenal Generation of Aldosterone Contributes to Ischemia-Induced Hypertension and Nephropathy in Mice
Ziwei Fu1, Chang-Jiang Zou1, Alex Kimball1
1Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, 84132, USA.
Background:
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.
Methods:
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).
Results:
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.
Conclusions:
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.
Insights
Intrarenal aldosterone (Aldo) biosynthesis, not just adrenal, contributes to kidney disease and hypertension. Targeting this intrarenal pathway offers a promising therapeutic strategy for these conditions.
Area of Science:
- Nephrology
- Endocrinology
- Cardiovascular Research
Background:
- Aldosterone (Aldo)-targeted therapies are advancing for resistant hypertension and chronic kidney disease.
- Aldo is traditionally considered an adrenal hormone, but its intrarenal role is increasingly recognized.
- The two-kidney, one-clip (2K1C) model is used to study renovascular hypertension and kidney injury.
Purpose of the Study:
- To investigate the role of intrarenal aldosterone biosynthesis in the pathogenesis of ischemic nephropathy and hypertension in the 2K1C model.
- To identify key regulators of intrarenal aldosterone production in this context.
- To evaluate the therapeutic potential of targeting intrarenal aldosterone synthesis.
Main Methods:
- Generated inducible renal tubule-specific C11B2 knockout (RT C11B2 KO) mice.
- Characterized the phenotype of RT C11B2 KO mice in the 2K1C model.
- Utilized collecting duct-specific (pro)renin receptor (CD PRR KO) and renin (CD renin KO) mice to explore mechanisms.
Main Results:
- Renal tubule-specific C11B2 deletion partially blocked hypertension but significantly improved renal fibrosis and inflammation post-2K1C.
- Intrarenal Aldo generation was blocked in RT C11B2 KO mice, while circulating Aldo levels remained unchanged.
- Collecting duct (pro)renin receptor and renin were identified as key upstream regulators of intrarenal Aldo biosynthesis in the 2K1C model.
Conclusions:
- Intrarenal aldosterone generation, regulated by CD PRR/renin, plays a crucial role in ischemic nephropathy and contributes to hypertension in renovascular constriction.
- Targeting intrarenal aldosterone biosynthesis may offer a more effective and safer therapeutic approach compared to current systemic aldosterone-targeted therapies.
- This study highlights a novel therapeutic avenue for managing ischemic kidney disease and associated hypertension.
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