ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-OR22

Critical Role of mTORC2 in Maintaining Sodium and Potassium Balance: Implications for Aldosterone-Independent Regulation of Epithelial Sodium Channel (ENaC) in the Distal Nephron

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

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

Authors

  • Saha, Bidisha, University of California San Francisco, San Francisco, California, United States
  • Demko, John Eric, University of California San Francisco, San Francisco, California, United States
  • Takagi, Enzo, University of California San Francisco, San Francisco, California, United States
  • Pearce, David, University of California San Francisco, San Francisco, California, United States
Background

mTOR complex-2 (mTORC2) is crucial for maintaining sodium and potassium balance in the kidneys and responding to high K+ ingestion. Recent evidence supports the idea that, in contrast to the late connecting tubule (CNT) and cortical collecting duct (CCD), ENaC activity in the late distal convoluted tubule (DCT2) and early CNT is not aldosterone-dependent. Here, we examined the role of mTORC2 in distal nephron K+ secretion by disrupting mTORC2 expression in various distal segments and examining its effects on potassium secretion during high dietary potassium conditions.

Methods

Rictor, a core component of mTORC2, was selectively knocked out (KO’d) in specific segments of the distal nephron or throughout the entire nephron using segment-specific Cre-Lox- KO techniques. Both WT and KO mice were fed a high K+ diet for short-term (4 h) or medium-term (48 h). Various parameters, including urinary and blood electrolytes, renal transporter expression and activity, and phosphorylation status of mTORC2 targets were assessed.

Results

Mice lacking mTORC2 in the DCT2 and CNT (using Calbindin as Cre-driver) responded to high K+ intake in a manner resembling mice in which Rictor was KO’d throughout the nephron (using Pax8/LC1): they developed hyperkalemia, increased urine output, elevated BUN levels, lower serum sodium, and elevated plasma aldosterone levels under both short (4 h) and medium (48 h)-term high K+ diet conditions. After 48 h under HK diet, these mice showed severe pathophysiological changes including weight loss, reduced food intake, markedly reduced GFR and listlessness. Phosphorylation of mTORC2 targets, involved in ENaC regulation (SGK1 and Nedd4-2) was also reduced in KO mice. Mice lacking mTORC2 specifically in the AQP2-expressing distal part of the CNT and CCD displayed a milder phenotype with elevated aldosterone but normal plasma [K+].

Conclusion

The data suggest that mTORC2 activity is crucial for maintaining aldosterone-independent ENaC activity in the late DCT and preserving potassium balance during high dietary potassium intake.

Funding

  • NIDDK Support