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

T. Tataranni, G. Biondi, M. Cariello, M. Mangino, G. Colucci, M. Rutigliano, P. Ditonno, F. P. Schena, L. Gesualdo, G. Grandaliano

Research output: Contribution to journalArticle

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Abstract

Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Because Klotho is an aging-suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin-induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser 473 expression directly correlating with long-term rapamycin exposure, FE PO4 and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation.

Original languageEnglish
Pages (from-to)1656-1664
Number of pages9
JournalAmerican Journal of Transplantation
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2011

Fingerprint

Hypophosphatemia
Sirolimus
Insulin Resistance
Phosphates
Homeostasis
TOR complex 2
Suppressor Genes
Immunosuppressive Agents
Kidney Transplantation
Healthy Volunteers
Animal Models
Phosphorylation

Keywords

  • Ageing
  • insulin resistance
  • kidney transplantation
  • rapamycin

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

Cite this

Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and klotho expression. / Tataranni, T.; Biondi, G.; Cariello, M.; Mangino, M.; Colucci, G.; Rutigliano, M.; Ditonno, P.; Schena, F. P.; Gesualdo, L.; Grandaliano, G.

In: American Journal of Transplantation, Vol. 11, No. 8, 08.2011, p. 1656-1664.

Research output: Contribution to journalArticle

Tataranni, T, Biondi, G, Cariello, M, Mangino, M, Colucci, G, Rutigliano, M, Ditonno, P, Schena, FP, Gesualdo, L & Grandaliano, G 2011, 'Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and klotho expression', American Journal of Transplantation, vol. 11, no. 8, pp. 1656-1664. https://doi.org/10.1111/j.1600-6143.2011.03590.x
Tataranni, T. ; Biondi, G. ; Cariello, M. ; Mangino, M. ; Colucci, G. ; Rutigliano, M. ; Ditonno, P. ; Schena, F. P. ; Gesualdo, L. ; Grandaliano, G. / Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and klotho expression. In: American Journal of Transplantation. 2011 ; Vol. 11, No. 8. pp. 1656-1664.
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