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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... Full description

Journal Title: Nature Medicine 2013-10, Vol.19 (10), p.1288-1296
Main Author: Canaud, Guillaume
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/24056770
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title: AKT2 is essential to maintain podocyte viability and function during chronic kidney disease
format: Article
creator:
  • 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
subjects:
  • Animals
  • Chronic illnesses
  • Chronic kidney failure
  • Disease Progression
  • Glomerular filtration rate
  • Humans
  • Kidney diseases
  • Kidney Failure, Chronic - metabolism
  • Kidney Failure, Chronic - pathology
  • Kidneys
  • Mechanistic Target of Rapamycin Complex 2
  • Metabolic disorders
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes - physiology
  • Nephrons - metabolism
  • Nephrons - physiopathology
  • Physiological aspects
  • Podocytes - cytology
  • Proto-Oncogene Proteins c-akt - genetics
  • Proto-Oncogene Proteins c-akt - physiology
  • TOR Serine-Threonine Kinases - physiology
ispartof: Nature Medicine, 2013-10, Vol.19 (10), p.1288-1296
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleAKT2 is essential to maintain podocyte viability and function during chronic kidney disease
creatorCanaud, 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
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descriptionIn 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.
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subjectAnimals ; Chronic illnesses ; Chronic kidney failure ; Disease Progression ; Glomerular filtration rate ; Humans ; Kidney diseases ; Kidney Failure, Chronic - metabolism ; Kidney Failure, Chronic - pathology ; Kidneys ; Mechanistic Target of Rapamycin Complex 2 ; Metabolic disorders ; Mice ; Mice, Knockout ; Multiprotein Complexes - physiology ; Nephrons - metabolism ; Nephrons - physiopathology ; Physiological aspects ; Podocytes - cytology ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - physiology ; TOR Serine-Threonine Kinases - physiology
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descriptionIn 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.
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titleAKT2 is essential to maintain podocyte viability and function during chronic kidney disease
authorCanaud, 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
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abstractIn 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.
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