Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury

Diabetes. 2013 Aug;62(8):2935-47. doi: 10.2337/db12-1504. Epub 2013 Apr 4.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenylate Kinase / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Line
  • Diabetic Nephropathies / metabolism*
  • Glucose / pharmacology*
  • Hypoglycemic Agents / pharmacology
  • Mice
  • NADPH Oxidase 4
  • NADPH Oxidases / metabolism*
  • Phosphorylation / drug effects
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • Reactive Oxygen Species / metabolism
  • Ribonucleotides / pharmacology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Hypoglycemic Agents
  • Reactive Oxygen Species
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Adenylate Kinase
  • AICA ribonucleotide
  • Glucose
  • Sirolimus