Kidney Week

Abstract: FR-PO530

FXR Modulates the Epithelial Sodium Channel Expression Through WNK1/SGK1/NEDD4-2 Signaling in the Kidney

Session Information

• Fluid, Electrolyte, Acid-Base Disorders: Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Li, Suchun, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Suchun Li,

• Ye, Siyang, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Siyang Ye,

• Fan, Yuting, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Yuting Fan,

• Li, Bin, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Bin Li,

• Li, Chunling, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, Guangdong, China

Chunling Li,

• Wang, Weidong, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, Guangdong, China

Weidong Wang,

• Chen, Wei, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Wei Chen,

Background

Epithelial sodium channel (ENaC), located in the aldosterone sensitive nephron, is essential for renal salt handling and blood-pressure homeostasis. The farnesoid X receptor (FXR) signaling is involved in various important physiological and pathophysiological processes in the kidney such as energy metabolism, immune responses and fluid homeostasis. Here, we aimed to investigate whether FXR is involved in regulating renal ENaC expression and the potential roles in angiotensin II-induced hypertension.

Methods

Immortalized mouse cortical collecting duct (mpkCCD_c14) cells and mice were treated with FXR agonists or antagonists. To induce hypertension, mice were infused with angiotensin II (300 ng/kg/min) for 2 weeks by osmotic minipump.

Results

We found that FXR activation by CDCA and INT-747 markedly decreased, whereas FXR antagonist guggulsterone increased the protein and mRNA expression levels of ENaC in the mpkCCD_c14 cells. CDCA reduced the amount of ENaC at the plasma membrane of mpkCCD_c14 cells, which indicated FXR activation inhibits the trafficking of ENaC to the cytomembrane. Interestingly, CDCA significantly reduced With-No-Lysine 1 (WNK1) and SGK1 expressions, whereas induced the E3 ubiquitin ligase NEDD4-2 expression. Additionally, immunofluorescence and immunoprecipitation revealed that the level of ubiquitin binding to ENaC was increased as a result of FXR activation. Consistent to the in vitro study, CDCA downregulated the expressions of ENaC in the kidney of mice, which was associated with increased abundance of WNK1 and SGK1 and decreased abundance of NEDD4-2. In angiotensin II-induced hypertension, CDCA treatment lowered the systolic and diastolic blood pressure in mice. The increased expressions of ENaC in the kidney induced by angiotensin II were prevented by CDCA through activation of NEDD4-2 signaling.

Conclusion

Our findings demonstrated FXR activation decreased renal ENaC expression likely through WNK1/SGK1/NEDD4-2 signaling and thus reduced blood-pressure in angiotensin II-induced hypertensive mice. FXR represents a promising target for the treatment of hypertension.

Funding

• Government Support – Non-U.S.