AKT2 is essential to maintain podocyte viability and function during chronic kidney disease.
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.
1] Institut National de la Santé et de la Recherche Médicale (INSERM) U845, Centre de Recherche 'Croissance et Signalisation', Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France. [2] Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, Paris, France. [3].
Guillaume
G
Canaud
Frank
F
Bienaimé
Amandine
A
Viau
Caroline
C
Treins
William
W
Baron
Clément
C
Nguyen
Martine
M
Burtin
Sophie
S
Berissi
Konstantinos
K
Giannakakis
Andrea Onetti
AO
Muda
Stefan
S
Zschiedrich
Tobias B
TB
Huber
Gérard
G
Friedlander
Christophe
C
Legendre
Marco
M
Pontoglio
Mario
M
Pende
Fabiola
F
Terzi
D000818:Animals; D018450:Disease Progression; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology; D009399:Nephrons / Q000378:metabolism / Q000503:physiopathology; D050199:Podocytes / Q000166:cytology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D046912:Multiprotein Complexes; C494922:Akt2 protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases