Activation of mTORC1 in Collecting Ducts Causes Hyperkalemia

Abstract

Mutation of TSC (encoding tuberous sclerosis complex protein) and activation of mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of several renal diseases, such as diabetic nephropathy and polycystic kidney disease. However, the role of mTOR in renal potassium excretion and hyperkalemia is not known. We showed that mice with collecting-duct (CD)-specific ablation of TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) activation in the CD and demonstrated features of pseudohypoaldosteronism, including hyperkalemia, hyperaldosteronism, and metabolic acidosis. mTORC1 activation caused endoplasmic reticulum stress, columnar cell lesions, and dedifferentiation of CD cells with loss of aquaporin-2 and epithelial-mesenchymal transition-like phenotypes. Of note, mTORC1 activation also reduced the expression of serum-and glucocorticoid-inducible kinase 1, a crucial regulator of potassium homeostasis in the kidney, and decreased the expression and/or activity of epithelial sodium channel-a, renal outer medullary potassium channel, and Na + , K + -ATPase in the CD, which probably contributed to the aldosterone resistance and hyperkalemia in these mice. Rapamycin restored these phenotypic changes. Overall, this study identifies a novel function of mTORC1 in regulating potassium homeostasis and demonstrates that loss of TSC1 and activation of mTORC1 results in dedifferentiation and dysfunction of the CD and causes hyperkalemia. The CDTsc1KO mice provide a novel model for hyperkalemia induced exclusively by dysfunction of the CD.

mTORC2 critically regulates renal potassium handling

“…Recent studies have suggested a role for mTOR signaling in tubular Na + and K + handling (20,25,26,39). Genetic deletion of TSC1 (which encodes tuberous sclerosis complex protein 1), with ensuing constitutive activation of mTORC1 in CDs, was associated with hyperkalemia (39).…”

Renal manifestation of tuberous sclerosis complex

“…Given these interactions between mTORC1 activity and cystogenesis, it is surprising that murine Tsc models are born with normal kidneys that later develop cysts with age. Investigations of both Tsc1 or Tsc2‐ associated renal cystic disease in the mouse directly (Armour, Carson, & Ess, ; Onda, Lueck, Marks, Warren, & Kwiatkowski, ; Zhou, Brugarolas, & Parada, ) or indirectly (Chen et al, ) demonstrate that cystogenesis is attributable to specific nephron segments, and all tubular segments have been implicated in murine Tsc cyst formation (Traykova‐Brauch et al, ). While all tubule segments probably could participate in cystogenesis, none of the published studies used a comprehensive panel of tubular segment markers to identify the cells involved.…”

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

“…) or indirectly (Chen et al. ) demonstrated that cystogenesis is attributable to specific nephron segments, and all tubular segments have been implicated in Tsc cyst formation (Traykova‐Brauch et al. ).…”

“…One such model has been reported to be associated with a potassium excretion defect (Chen et al. ). Early investigation revealed that the majority of renal cysts maintain their Tsc locus integrity (Onda et al.…”