AKT2 is essential to maintain podocyte viability and function during chronic kidney disease

Nat Med. 2013 Oct;19(10):1288-96. doi: 10.1038/nm.3313. Epub 2013 Sep 22.

Abstract

In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Progression
  • Humans
  • Kidney Failure, Chronic / metabolism*
  • Kidney Failure, Chronic / pathology
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / physiology
  • Nephrons / metabolism
  • Nephrons / physiopathology
  • Podocytes / cytology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / physiology*
  • TOR Serine-Threonine Kinases / physiology

Substances

  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Akt2 protein, mouse
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt