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

被引：181

作者：

Canaud, Guillaume ^{[1
,2
]}

Bienaime, Frank ^{[1
,3
]}

Viau, Amandine ^{[1
]}

Treins, Caroline ^{[1
]}

Baron, William ^{[1
]}

Nguyen, Clement ^{[1
]}

Burtin, Martine ^{[1
]}

Berissi, Sophie ^{[1
]}

Giannakakis, Konstantinos ^{[4
]}

Muda, Andrea Onetti ^{[5
]}

Zschiedrich, Stefan ^{[6
,7
]}

Huber, Tobias B. ^{[6
,7
]}

Friedlander, Gerard ^{[1
,3
]}

Legendre, Christophe ^{[1
,2
]}

Pontoglio, Marco ^{[8
]}

Pende, Mario ^{[1
]}

Terzi, Fabiola ^{[1
]}

机构：

[1] Univ Paris 05, Hop Necker Enfants Malad, INSERM U845, Ctr Rech Croissance & Signalisat,Sorbonne Paris C, Paris, France

[2] Hop Necker Enfants Malad, Serv Nephrol Transplantat Adultes, Paris, France

[3] Hop Necker Enfants Malad, Serv Physiol Explorat Fonctionnelles, Paris, France

[4] Univ Roma La Sapienza, Dept Radiol Oncol & Pathol, I-00185 Rome, Italy

[5] Campus Biomed Univ, Dept Pathol, Rome, Italy

[6] Univ Hosp Freiburg, Renal Div, Freiburg, Germany

[7] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79106 Freiburg, Germany

[8] Univ Paris 05, Inst Cochin, INSERM U1016, CNRS UMR 8104, Paris, France

来源：

NATURE MEDICINE | 2013年 / 19卷 / 10期

关键词：

FOCAL SEGMENTAL GLOMERULOSCLEROSIS; DIABETIC-NEPHROPATHY; NEPHROTIC-SYNDROME; PROTEIN-KINASE; GLUCOSE-HOMEOSTASIS; ACTIN CYTOSKELETON; INSULIN-RESISTANCE; MTORC1; ACTIVATION; RENAL-DISEASE; MICE LACKING;

D O I：

10.1038/nm.3313

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1288 / +

页数：11

共 61 条

[1] Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis [J].