Mechanistic target of rapamycin complex-1 plays a role in inhibiting kidney K+ excretion during overnight dietary K+ restriction.

Decreased dietary K+ intake stimulates the expression of regulatory-associated protein of mTOR (RAPTOR) in kidneys and increases mRNA of Raptor in aldosterone-sensitive distal nephrons. The aim of the study is to explore the role of mechanistic target of rapamycin complex-1 (mTORc1) in stimulating Kir4.1/Kir5.1 and Na-Cl cotransporter (NCC), and inhibiting renal outer medullary K+ channel (ROMK or Kir1.1) and epithelial-Na+ channel (ENaC) during overnight low K+ intake (LK). Deletion of RAPTOR in kidneys inhibited basolateral Kir4.1/Kir5.1 of distal convoluted tubule (DCT) and decreased the expression of phosphor-NCC and total-NCC. Furthermore, ENaC and ROMK baseline activity in late DCT/early connecting tubule (CNT) and cortical collecting duct (CCD) of kidney tubule-specific RAPTOR knockout mice (Ks-RAPTOR-KO) were higher than Raptorflox/flox mice. Consequently, Ks-RAPTOR-KO mice had higher baseline kidney K+ excretion and lower plasma K+ concentrations than Raptorflox/flox mice. Overnight LK intake stimulated Kir4.1/Kir5.1 activity of DCT and the expression of phosphor-NCC and total-NCC in Raptorflox/flox mice. In contrast, overnight LK failed to stimulate Kir4.1/Kir5.1 of the DCT and did not increase the expression of phosphor-NCC and total-NCC in Ks-RAPTOR-KO mice. Moreover, overnight LK inhibits ROMK and ENaC in late DCT/early CNT and CCD only in Raptorflox/flox mice but not in Ks-RAPTOR-KO mice. Thus, male/female Ks-RAPTOR-KO mice on overnight LK had lower plasma K+ levels and higher kidney K+ excretion than Raptorflox/flox mice. We conclude that mTORc1 plays a key role in suppressing kidney K+ excretion during decreased dietary K+ intake.NEW & NOTEWORTHY We demonstrate that mechanistic target of rapamycin complex-1 (mTORc1) plays a key role in preventing excessive K+ waste during decreased dietary K+ intake by stimulating Kir4.1/Kir5/1 and inhibiting epithelial-Na+ channel (ENaC) and renal outer medullary K+ channel (ROMK) in aldosterone-sensitive distal nephron (ASDN). Thus, mechanistic target of rapamycin (mTOR) signaling pathway is essential for maintaining body K+ homeostasis under control conditions and during low dietary K+ intake.