NYMC Faculty Publications

Mtorc2 in Distal Convoluted Tubule and Renal K1 Excretion During High Dietary K1 Intake

Author Type(s)

Faculty

DOI

10.1681/ASN.0000000000000406

Journal Title

Journal of the American Society of Nephrology

First Page

1149

Last Page

1163

Document Type

Article

Publication Date

9-1-2024

Department

Pharmacology

Disciplines

Medicine and Health Sciences

Abstract

Background Renal mechanistic target of rapamycin complex 2 (mTORc2) plays a role in regulating renal K1 excretion (renal-EK) and K1 homeostasis. Inhibition of renal mTORc2 causes hyperkalemia due to suppressing epithelial Na1 channel and renal outer medullary K1 (Kir1.1) in the collecting duct. We now explore whether mTORc2 of distal convoluted tubules (DCTs) regulates basolateral Kir4.1/Kir5.1, Na-Cl cotransporter (NCC), and renal-EK. Methods We used patch-clamp technique to examine basolateral Kir4.1/Kir5.1 in early DCT, immunoblotting, and immunofluorescence to examine NCC expression and in vivo measurement of urinary K1 excretion to determine baseline renal-EK in mice treated with an mTORc2 inhibitor and in DCT-specific rapamycin-insensitive companion of mTOR knockout (DCT-RICTOR-KO) mice. Results Inhibition of mTORc2 with AZD8055 abolished high-K1–induced inhibition of Kir4.1/Kir5.1 in DCT, high potassium–induced depolarization of the DCT membrane, and high potassium–induced suppression of phosphorylated Na-Cl cotransporter (pNCC) expression. AZD8055 stimulated the 40-pS inwardly rectifying K1 channel (Kir4.1/Kir5.1-heterotetramer) in early DCT in the mice on overnight high potassium intake; this effect was absent in the presence of protein kinase C inhibitors, which also stimulated Kir4.1/Kir5.1. AZD8055 treatment decreased renal-EK in animals on overnight high-potassium diet. Deletion of RICTOR in the DCT increased the Kir4.1/Kir5.1-mediated K1 currents, hyperpolarized the DCT membrane, and increased the expression of pWNK4 and pNCC. Renal-EK was lower and plasma K1 was higher in DCT-RICTOR-KO mice than corresponding control mice. In addition, overnight high-potassium diet did not inhibit Kir4.1/Kir5.1 activity in the DCT and failed to inhibit the expression of pNCC in DCT-RICTOR-KO mice. Overnight high potassium intake stimulated renal-EK in control mice, but this effect was attenuated in DCT-RICTOR-KO mice. Thus, overnight high potassium intake induced hyperkalemia in DCT-RICTOR-KO mice but not in control mice. Conclusions mTORc2 of the DCT inhibits Kir4.1/Kir5.1 activity and NCC expression and stimulates renal-EK during high potassium intake.

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