Journal article
Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy
Diabetes (New York, N.Y.), Vol.63(2), pp.701-714
02/2014
DOI: 10.2337/db13-0752
PMCID: PMC3900538
PMID: 24101677
Abstract
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.
Details
- Title: Subtitle
- Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy
- Creators
- Johanna Guzman - Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FLAlexandra N JaureguiSandra Merscher-GomezDony MaiguelCristina MuresanAlla MitrofanovaAna Diez-SampedroJoel SzustTae-Hyun YooRodrigo VillarrealChristopher PedigoR Damaris MolanoKevin JohnsonBarbara KahnBjoern HartlebenTobias B HuberJharna SahaGeorge W Burke IIIE Dale AbelFrank C BrosiusAlessia Fornoni
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.63(2), pp.701-714
- Publisher
- United States
- DOI
- 10.2337/db13-0752
- PMID
- 24101677
- PMCID
- PMC3900538
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Grant note
- P30 DK020572 / NIDDK NIH HHS R01 DK090316 / NIDDK NIH HHS U01 HL087947 / NHLBI NIH HHS UL1 TR000460 / NCATS NIH HHS P30 DK092926 / NIDDK NIH HHS R37 DK043051 / NIDDK NIH HHS R01 DK043051 / NIDDK NIH HHS
- Language
- English
- Date published
- 02/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025299902771
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