Kidney Week

Abstract: SA-PO0476

mTORc2 Stimulates Renal Potassium (K+) Excretion During Overnight-High-K+ by Simultaneously Stimulating Epithelial Sodium Channel (ENaC)/Potassium Kir1.1 Channel (ROMK) and Inhibiting Kir4.1/Kir5.1

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  November 08, 2025 | Location: Exhibit Hall, 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

Author

• Wang, Wen-Hui, New York Medical College, Valhalla, New York, United States

Wen-Hui Wang, MD

Background

The mTORc2 is a multiprotein complex and RICTOR (rapamycin insensitive companion of mTOR) is one of the core components of mTORc2. Previous studies have demonstrated the role of mTORc2 in regulating renal K⁺ -excretion by modulating Kir4.1/Kir5.1 in the distal convoluted tubule (DCT), regulating ENaC and ROMK in the collecting duct. The aim of the study is to examine whether overnight-high-K⁺-intake-induced stimulation of renal K⁺-excretion is achieved by simultaneous initiation of mTORc2 -dependent inhibition of Kir4.1/Kir5.1 in the DCT and mTORc2-dependent stimulation of ENaC and ROMK in the late distal tubules.

Methods

We performed patch-clamp experiments, immunoblotting, metabolic cage and in vivo measurement of urinary-K⁺-excretion in kidney-tubule-specific RICTOR (Rapamycin-insensitive-companion of mTOR) knockout mice (Ks-RICTOR-KO) and corresponding wild-type mice (Rictor^flox/flox).

Results

Ks-RICTOR-KO mice had a lower urinary K⁺-excretion and higher plasma K⁺ concentration than Rictor^flox/flox mice. Moreover, overnight high-K⁺ intake further increased plasma K⁺ level in Ks-RICTOR-KO mice but not in Rictor^flox/flox mice. Ks-RICTOR-KO mice had higher basolateral Kir4.1/Kir5.1 activity in the DCT than Rictor^flox/flox mice. In contrast, amiloride-sensitive Na⁺-currents (ENaC) and tertiapin-Q (TPNQ)-sensitive-K⁺-currents (ROMK) were lower in both late-DCT/early-connecting-tubule (CNT) and cortical- collecting-duct (CCD) of Ks-RICTOR-KO mice than Rictor^flox/flox mice. Overnight high-K⁺ intake decreased Kir4.1/Kir5.1 activity of DCT and increased amiloride-sensitive Na⁺-currents and TPNQ-sensitive K⁺ currents in late-DCT/early-CNT and in the CCD in Rictor^flox/flox mice. However, these effects of overnight-high-K⁺ were absent in Ks-RICTOR-KO mice. Finally, in vivo measurement-of-urinary-K⁺- excretion showed that urinary K⁺-excretion in Ks-RICTOR-KO mice on overnight-high-K was lower than Rictor^flox/flox mice.

Conclusion

The mTORc2 plays a role in maintaining baseline-activity of Kir4.1/Kir5.1, ROMK and ENaC. It mediates the effect of high-K⁺-intake on ENaC and ROMK not only in the CCD but also in late-DCT/early-CNT. The mTORc2 plays a key role in stimulating renal K⁺ excretion during high-K⁺-loading by simultaneously inhibiting Kir4.1/Kir5.1 and stimulating ENaC and ROMK.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.202561xfw196