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Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression

T Tataranni1, G Biondi, M Cariello

  • 1Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari 'A. Moro', Italy.

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
|June 16, 2011
PubMed

Insights

Rapamycin, an immunosuppressive drug, affects phosphate balance and insulin resistance by modulating Klotho expression via mTORC2 activation. This study reveals a potential mechanism linking rapamycin

Area of Science:

  • Nephrology
  • Endocrinology
  • Aging Research

Background:

  • Rapamycin is an immunosuppressant used in kidney transplantation, known to affect phosphate homeostasis, insulin sensitivity, and lifespan.
  • Klotho is an aging-suppressor gene crucial for phosphate metabolism and insulin sensitivity.
  • The interaction between rapamycin and Klotho expression remains incompletely understood.

Purpose of the Study:

  • To investigate the influence of rapamycin on Klotho expression in kidney transplant recipients.
  • To explore the underlying molecular mechanisms, particularly the role of mTORC2 signaling.
  • To correlate rapamycin's effects on phosphate homeostasis and insulin resistance with Klotho levels.

Main Methods:

  • Comparison of 100 kidney transplant recipients (50 on rapamycin, 50 on calcineurin inhibitors) and 20 healthy controls.
  • Measurement of serum phosphate, phosphate excretion, reabsorption, and insulin resistance (HOMA index).
  • In vitro studies using a proximal tubular cell line treated with rapamycin, assessing Klotho, AKT, and RICTOR expression, with and without AKT inhibition.
  • In vivo analysis of RICTOR and AKT phosphorylation correlating with rapamycin exposure and metabolic parameters.

Main Results:

  • The rapamycin group exhibited lower serum phosphate, increased phosphate excretion, and reduced reabsorption compared to the calcineurin inhibitor group.
  • Rapamycin treatment increased insulin resistance, as indicated by the HOMA index.
  • In vitro, rapamycin induced Klotho expression, AKT phosphorylation at Ser473, and RICTOR expression, effects partially reversed by AKT inhibition.
  • In vivo, RICTOR and AKT phosphorylation correlated with duration of rapamycin treatment, phosphate excretion, and HOMA index.

Conclusions:

  • Rapamycin may influence phosphate homeostasis and insulin resistance by modulating Klotho expression.
  • The mTORC2 pathway, involving RICTOR and AKT, appears to be a key mediator in this process.
  • These findings suggest a novel mechanism by which rapamycin exerts its metabolic effects.

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