Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy

Johanna Guzman, Alexandra N. Jauregui, Sandra Merscher-Gomez, Dony Maiguel, Cristina Muresan, Alla Mitrofanova, Ana Diez-Sampedro, Joel Szust, Tae Hyun Yoo, Rodrigo Villarreal, Christopher Pedigo, R. Damaris Molano, Kevin Johnson, Barbara Kahn, Bjoern Hartleben, Tobias B. Huber, Jharna Saha, George W. Burke, E. Dale Abel, Frank C. BrosiusAlessia Fornoni

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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 wildtype (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 adriamycininduced 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.

Original languageEnglish
Pages (from-to)701-714
Number of pages14
JournalDiabetes
Volume63
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

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All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Guzman, J., Jauregui, A. N., Merscher-Gomez, S., Maiguel, D., Muresan, C., Mitrofanova, A., Diez-Sampedro, A., Szust, J., Yoo, T. H., Villarreal, R., Pedigo, C., Molano, R. D., Johnson, K., Kahn, B., Hartleben, B., Huber, T. B., Saha, J., Burke, G. W., Abel, E. D., ... Fornoni, A. (2014). Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy. Diabetes, 63(2), 701-714. https://doi.org/10.2337/db13-0752