AKT2 is essential to maintain podocyte viability and function during chronic kidney disease
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AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. / Canaud, Guillaume; Bienaimé, Frank; Viau, Amandine; Treins, Caroline; Baron, William; Nguyen, Clément; Burtin, Martine; Berissi, Sophie; Giannakakis, Konstantinos; Muda, Andrea Onetti; Zschiedrich, Stefan; Huber, Tobias B; Friedlander, Gérard; Legendre, Christophe; Pontoglio, Marco; Pende, Mario; Terzi, Fabiola.
In: NAT MED, Vol. 19, No. 10, 10.2013, p. 1288-96.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - AKT2 is essential to maintain podocyte viability and function during chronic kidney disease
AU - Canaud, Guillaume
AU - Bienaimé, Frank
AU - Viau, Amandine
AU - Treins, Caroline
AU - Baron, William
AU - Nguyen, Clément
AU - Burtin, Martine
AU - Berissi, Sophie
AU - Giannakakis, Konstantinos
AU - Muda, Andrea Onetti
AU - Zschiedrich, Stefan
AU - Huber, Tobias B
AU - Friedlander, Gérard
AU - Legendre, Christophe
AU - Pontoglio, Marco
AU - Pende, Mario
AU - Terzi, Fabiola
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Animals
KW - Disease Progression
KW - Humans
KW - Kidney Failure, Chronic
KW - Mice
KW - Mice, Knockout
KW - Multiprotein Complexes
KW - Nephrons
KW - Podocytes
KW - Proto-Oncogene Proteins c-akt
KW - TOR Serine-Threonine Kinases
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/nm.3313
DO - 10.1038/nm.3313
M3 - SCORING: Journal article
C2 - 24056770
VL - 19
SP - 1288
EP - 1296
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 10
ER -