KLOTHO DEFICIENCY AND IMPAIRED POTASSIUM HOMEOSTASIS: INVOLVEMENT OF mTORC1 SIGNALING

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KLOTHO DEFICIENCY AND IMPAIRED POTASSIUM HOMEOSTASIS: INVOLVEMENT OF mTORC1 SIGNALING

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Co-author 1

Wakako Kawarazaki wkawarazaki-tky@umin.ac.jp International University of Health and Welfare Center for Basic Medical Research Narita Japan *

Co-author 2

Nobuhiro Ayuzawa ayuzawa-tky@umin.ac.jp Research Center for Advanced Science and Technology, The University of Tokyo Division of Clinical Epigenetics Tokyo Japan -

Co-author 3

Mitsuhiro Nishimoto nishimoto-tky@umin.ac.jp Research Center for Advanced Science and Technology, The University of Tokyo Division of Clinical Epigenetics Tokyo Japan -

Co-author 4

Daigoro Hirohama hirohama-tky@umin.ac.jp Research Center for Advanced Science and Technology, The University of Tokyo Division of Clinical Epigenetics Tokyo Japan -

Co-author 5

Takeshi Marumo tmarumo-npr@umin.ac.jp School of Medicine, International University of Health and Welfare Department of Molecular Biology Narita Japan -

Co-author 6

Toshiro Fujita Toshiro.FUJITA@rcast.u-tokyo.ac.jp Research Center for Advanced Science and Technology, The University of Tokyo Division of Clinical Epigenetics Tokyo Japan -

Co-author 7

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Introduction

Hyperkalemia is a common electrolyte disturbance associated with poor prognosis. It frequently occurs in patients with chronic kidney disease, particularly in older adults, and is linked to reduced levels of the anti-aging factor Klotho. This study aims to investigate the relationship between hyperkalemia and Klotho deficiency.

Methods

In Klotho heterozygous knockout (KLKO) mice, we measured serum potassium levels, urinary potassium excretion, and the membrane expression of renal outer medullary potassium channel 1 (ROMK1), as well as cleaved α- and γ-subunits of the epithelial sodium channel (ENaC). Plasma aldosterone concentration (PAC) and phosphorylated S6 kinase (p-S6K), a downstream target of mechanistic target of rapamycin complex 1 (mTORC1), were also evaluated.

Results

KLKO mice exhibited mild but significant hyperkalemia and reduced urinary potassium excretion, along with decreased membrane ROMK1 expression. Aldosterone production was elevated, as shown by increased PAC and adrenal Cyp11b2 expression, accompanied by enhanced cleavage of α- and γ-ENaC. Severe hyperkalemia was induced by administration of the ENaC inhibitor amiloride. Renal p-S6K expression was elevated in KLKO mice. Treatment with rapamycin or Klotho supplementation restored ROMK1 expression and serum potassium levels, while suppressing Cyp11b2 expression, PAC, and ENaC activation.

Conclusion

Klotho deficiency activates renal mTORC1 signaling, leading to ROMK1 downregulation and impaired urinary potassium excretion, thereby contributing to hyperkalemia. In parallel, increased aldosterone production and ENaC activation partially compensate for the impaired potassium excretion and mitigate the elevation in serum potassium levels. Thus, ENaC inhibition under Klotho deficiency can provoke severe hyperkalemia. These findings suggest that Klotho supplementation and mTORC1 inhibition may represent potential therapeutic strategies for preventing hyperkalemia in Klotho-deficient states.

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