Mammalian target of rapamycin regulates nox4-Mediated podocyte depletion in diabetic renal injury

Assaad A. Eid, Bridget M. Ford, Basant Bhandary, Rita De Cassia Cavaglieri, Karen Block, Jeffrey L. Barnes, Yves Gorin, Goutam Ghosh Choudhury, Hanna E. Abboud

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Pharmacological doses of the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduce albuminuria in diabetes. We explored the hypothesis that mTOR mediates podocyte injury in diabetes. High glucose (HG) induces apoptosis of podocytes, inhibits AMPactivated protein kinase (AMPK) activation, inactivates tuberin, and activates mTOR. HG also increases the levels of Nox4 and Nox1 and NADPH oxidase activity. Inhibition of mTOR by lowdose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase activity, and podocyte apoptosis. Inhibition of mTOR had no effect on AMPK or tuberin phosphorylation, indicating that mTOR is downstream of these signaling molecules. In isolated glomeruli of OVE26 mice, there is a similar decrease in the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 and NADPH oxidase activity. Inhibition of mTOR by a small dose of rapamycin reduces podocyte apoptosis and attenuates glomerular injury and albuminuria. Our data provide evidence for a novel function of mTOR in Nox4-derived reactive oxygen species generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes. Thus, mTOR and/or NADPH oxidase inhibition may represent a therapeutic modality of diabetic kidney disease.

Original languageEnglish (US)
Pages (from-to)2935-2947
Number of pages13
JournalDiabetes
Volume62
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Fingerprint Dive into the research topics of 'Mammalian target of rapamycin regulates nox4-Mediated podocyte depletion in diabetic renal injury'. Together they form a unique fingerprint.

Cite this