Abstract: TH-PO1085
Renal Tubule-Specific Deletion of Aldosterone Synthase CYP11B2 Improves 2-Kidney, 1-Clip-Induced Ischemic Nephropathy, and Renovascular Hypertension in Mice
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Fu, Ziwei, University of Utah Health, Salt Lake City, Utah, United States
- Zou, Changjiang, University of Utah Health, Salt Lake City, Utah, United States
- Yang, Tianxin, University of Utah Health, Salt Lake City, Utah, United States
Background
Although the intrarenal renin-angiotensin system (RAS) has been well established, evidence for intrarenal generation of aldosterone (Aldo) is scarce and therefore Aldo is often omitted in the intrarenal RAS. The co-expression of renin and its receptor (pro)renin receptor (PRR) in the collecting duct (CD) constitutes a key component of the intrarenal RAS.
Methods
In the present study, mice carrying inducible Pax8-rtTA-LC1-Cre were crossed with CYP11B2 floxed mice to generate a novel mouse model of renal tubules-specific deletion of CYP11B2 (RT CYP11B2 KO), born at the expected Mendelian ratio without noticeable developmental abnormalities. CD-specific deletion of PRR (CD PRR KO) or renin (CD renin KO), RT CYP11B2 KO mice and related floxed mice were subjected to sham or 2K1C procedure, followed by radiotelemetry analysis of blood pressure (BP), renal injury, and indices of the Aldo, as well as the expression of subunits of ENaC.
Results
Clipping-induced hypertension and renal injury were both attenuated in RT CYP11B2 KO mice as compared with floxed controls (MAP on day 24: Floxed/2K1C 151.2±4.9 mmHg vs. RT CYP11B2 KO/2K1C 135.3±3.6 mmHg, n=7, p < 0.05) (urinary albumin/creatinine: Floxed/2K1C 69.7±4.8 mg/g vs. RT CYP11B2 KO/2K1C 34.2±3.8 mg/g, n=7, p < 0.01). Clipping-induced upregulation of renal fibronectin and α-SMA was blunted in RT CYP11B2 KO mice by 54% and 50%, respectively. Similarly, clipping induced paralleled increases in renal mRNA expression of IL-1β, TNF-α, MCP-1 and TGF-β1 were all blunted in RT CYP11B2 KO mice. The protective phenotype of RT CYP11B2 KO mice were paralleled with suppressed urinary Aldo level (urinary Aldo excretion: Floxed/2K1C 9.8±0.7 ng/24h vs. RT CYP11B2 KO/2K1C 2.2±0.3 ng/24h, n=7, p < 0.01). In contrast, clipping-induced enhancement of circulating Aldo remained unchanged between the genotypes. Moreover, renal medullary α-ENaC mRNA expression was elevated by clipping in floxed mice, which was blunted by 51% in RT CYP11B2 KO mice. CD PRR KO mice and CD renin KO mice exhibited similar improvements in renal injury and hypertension, which was paralleled with suppressed intrarenal Aldo levels.
Conclusion
Together, these results provide genetic evidence for pathogenic role of intrarenal Aldo in renovascular hypertension and ischemic nephropathy.
Funding
- NIDDK Support