Klotho Deficiency Impairs Distal Potassium Homeostasis Through mTORC1 ‐Dependent Suppression of ROMK

ABSTRACT Aim Hyperkalemia is prevalent in the elderly, and underlying molecular mechanisms remain incompletely understood. We hypothesized that Klotho deficiency, a feature of aging, impairs renal potassium homeostasis and contributes to hyperkalemia. Methods Klotho heterozygous knockout (KLhet) mice, characterized by reduced Klotho levels, were used to investigate determinants of potassium handling, including renal outer medullary potassium channel (ROMK)1, the epithelial sodium channel (ENaC), which provides the driving force for ROMK‐mediated potassium secretion, and plasma aldosterone concentration (PAC). Results KLhet mice developed hyperkalemia with reduced urinary potassium excretion, accompanied by activation of renal mechanistic target of rapamycin complex 1 (mTORC1) signaling, indicated by increased phosphorylated S6, and decreased ROMK1 abundance in the plasma membrane fraction. Adrenal expression of aldosterone synthase Cyp11b2 and PAC were elevated, and ENaC activity was enhanced, as evidenced by increased cleavage of α‐ and γ‐ENaC subunits, partially compensating for impaired potassium excretion. Pharmacological ENaC inhibition with amiloride precipitated severe hyperkalemia in KLhet mice. In contrast, treatment with the mTORC1 inhibitor rapamycin or Klotho supplementation suppressed renal mTORC1 signaling, restored plasma membrane ROMK1 abundance, increased urinary potassium excretion, and normalized serum potassium levels, with reduced Cyp11b2 expression. Conclusion Klotho deficiency impairs renal potassium handling through mTORC1‐dependent downregulation of ROMK, with compensatory hyperaldosteronism and ENaC activation. These findings highlight an important role of the Klotho–mTORC1 axis in distal potassium homeostasis and its potential as a therapeutic target for Klotho deficiency–associated hyperkalemia.