Mammalian Target of Rapamycin Regulates Nox4-Mediated Podocyte Depletion in Diabetic Renal Injury
- Assaad A. Eid1,2⇑,
- Bridget M. Ford1,
- Basant Bhandary1,
- Rita de Cassia Cavaglieri1,
- Karen Block1,
- Jeffrey L. Barnes1,
- Yves Gorin1,
- Goutam Ghosh Choudhury1 and
- Hanna E. Abboud1
- 1Department of Medicine, South Texas Veterans Healthcare System and the University of Texas Health Science Center, San Antonio, Texas;
- 2Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Corresponding author: Assaad A. Eid, .
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 AMP-activated 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 low-dose 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1504/-/DC1.
- Received October 30, 2012.
- Accepted March 29, 2013.
- © 2013 by the American Diabetes Association.
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