Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy
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Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy. / Guzman, Johanna; Jauregui, Alexandra N; Merscher-Gomez, Sandra; Maiguel, Dony; Muresan, Cristina; Mitrofanova, Alla; Diez-Sampedro, Ana; Szust, Joel; Yoo, Tae-Hyun; Villarreal, Rodrigo; Pedigo, Christopher; Molano, R Damaris; Johnson, Kevin; Kahn, Barbara; Hartleben, Bjoern; Huber, Tobias B; Saha, Jharna; Burke, George W; Abel, E Dale; Brosius, Frank C; Fornoni, Alessia.
In: DIABETES, Vol. 63, No. 2, 02.2014, p. 701-14.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy
AU - Guzman, Johanna
AU - Jauregui, Alexandra N
AU - Merscher-Gomez, Sandra
AU - Maiguel, Dony
AU - Muresan, Cristina
AU - Mitrofanova, Alla
AU - Diez-Sampedro, Ana
AU - Szust, Joel
AU - Yoo, Tae-Hyun
AU - Villarreal, Rodrigo
AU - Pedigo, Christopher
AU - Molano, R Damaris
AU - Johnson, Kevin
AU - Kahn, Barbara
AU - Hartleben, Bjoern
AU - Huber, Tobias B
AU - Saha, Jharna
AU - Burke, George W
AU - Abel, E Dale
AU - Brosius, Frank C
AU - Fornoni, Alessia
PY - 2014/2
Y1 - 2014/2
N2 - Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria.
AB - Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria.
KW - Albuminuria
KW - Animals
KW - Cell Size
KW - Diabetic Nephropathies
KW - Doxorubicin
KW - Female
KW - Gene Expression Regulation
KW - Glomerular Filtration Barrier
KW - Glucose Transporter Type 1
KW - Glucose Transporter Type 4
KW - Lipopolysaccharides
KW - Mice
KW - Podocytes
KW - Journal Article
U2 - 10.2337/db13-0752
DO - 10.2337/db13-0752
M3 - SCORING: Journal article
C2 - 24101677
VL - 63
SP - 701
EP - 714
JO - DIABETES
JF - DIABETES
SN - 0012-1797
IS - 2
ER -