Activation of mTORC1 in collecting ducts causes hyperkalemia

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Tuberous sclerosis complex (TSC) protein mutations and mammalian target of rapamycin (mTOR) activation are linked to kidney diseases.
• The specific role of mTOR in renal potassium excretion and hyperkalemia remains uncharacterized.

Purpose of the Study:

• To investigate the role of mTOR signaling in the kidney's collecting duct (CD) in regulating potassium homeostasis.
• To determine the consequences of TSC1 loss and subsequent mTOR activation in the CD.

Main Methods:

• Utilized collecting-duct-specific ablation of TSC1 in mice (CDTsc1KO) to induce mTOR complex 1 (mTORC1) activation.
• Analyzed features of pseudohypoaldosteronism, including hyperkalemia, hyperaldosteronism, and metabolic acidosis.
• Assessed cellular changes such as endoplasmic reticulum stress, cell dedifferentiation, and expression of key ion transporters.

Main Results:

• CDTsc1KO mice exhibited increased mTORC1 activation, hyperkalemia, hyperaldosteronism, and metabolic acidosis.
• mTORC1 activation led to CD cell dedifferentiation, loss of aquaporin-2, and endoplasmic reticulum stress.
• Reduced expression of serum- and glucocorticoid-inducible kinase 1 and key CD ion transporters (e.g., ENaC-α, ROMK, Na+/K+-ATPase) were observed.
• Rapamycin treatment reversed these phenotypic alterations.

Conclusions:

• mTORC1 plays a novel role in regulating renal potassium homeostasis.
• Loss of TSC1 and subsequent mTORC1 activation cause collecting duct dysfunction and hyperkalemia.
• CDTsc1KO mice represent a valuable model for studying hyperkalemia resulting from isolated collecting duct dysfunction.