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Kidney Week

Abstract: TH-PO486

Collecting Duct-Specific Deletion of Renin Attenuates Obstruction-Induced Renal Fibrosis and Inflammation

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Luo, Renfei, University of Utah, Salt Lake City, Utah, United States
  • Yang, Kevin, University of Utah, Salt Lake City, Utah, United States
  • Xu, Chuanming, University of Utah, Salt Lake City, Utah, United States
  • Wang, Fei, University of Utah, Salt Lake City, Utah, United States
  • Yang, Tianxin, University of Utah, Salt Lake City, Utah, United States
Background

Increasing evidence demonstrates that renin is synthesized and secreted by the collecting duct (CD) as a component of the intrarenal renin-angiotensin system (RAS). The intarenal RAS is well known to contribute to the pathogenesis of chronic renal disease (CKD) in addition to hypertension. However, the precise mechanism of how intrarenal RAS is activated in the disease process is poorly characterized.

Methods

The goal of the present study was to examine the impact of CD-specific deletion of renin on renal fibrosis and inflammation in a mouse model of unilateral ureteral obstruction (UUO). CD-specific renin deletion was generated by crossing aquaporin-2-Cre mice with renin floxed mice (CD renin KO). UUO was performed by ligation of the left ureter near the renal pelvis in flox mice and CD renin KO mice.

Results

After 3 days of UUO, the renal medullary renin content, renin activity and renin mRNA in obstructed kidneys of flox mice were increased by 4.7-, 2.2- and 7.8-fold, respectively, which were all blocked by CD renin KO mice. In contrast, renal cortical renin was largely unaffected by UUO, irrespective of the genotype. Meanwhile, CD renin KO decreased the α-SMA (51.3±10.9%) and fibronectin (60.4±7.2%) protein expression and increased E-cadherin (2.1-fold) protein expression in obstructed kidneys. The content of hydroxyproline, a major component of the protein collagen, in obstructed kidneys of CD renin KO mice showed a significantly reduced generation compared with obstructed kidneys of flox mice. (KO+UUO: 7.7±0.9 versus flox+UUO: 12.3±1.6 ug/mg tissue; P<0.05). The Masson's trichrome staining (MST) data also showed that CD renin KO significantly attenuated UUO-induced collagen deposition and histological damage in the kidney. In parallel, CD renin KO reduced α-SMA (48.2±4.3%), fibronectin (38.6±7.4%), TGF-β (32.9±6.7%), IL-6 (20.6±6.1%) and TNF-α (47.2±5.2%) mRNA expression in obstructed kidneys.

Conclusion

Overall, these results suggest that overactivation of renal CD renin plays an essential role in driving local RAS to promote renal fibrosis induced by obstruction.

Funding

  • NIDDK Support