mTOR Regulates Nox4-Mediated Podocyte Depletion in Diabetic Renal Injury.
Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Pharmacological doses of the mTOR inhibitor rapamycin reduce albuminura in diabetes. We explored the hypothesis that mTOR mediates podocyte injury in diabetes. High glucose (HG) induces apoptosis of podocytes, inhibits 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 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 small dose of rapamycin reduces podocyte apoptosis, attenuates glomerular injury and albuminuria. Our data provide evidence for a novel function of mTOR in Nox4-derived ROS 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.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y
NADPH rapamycin glucose NADPH rapamycin NADPH NADPH rapamycin mTOR Nox4 albumin mTOR NADPH oxidase mTOR mTOR AMPK tuberin mTOR Nox4 Nox1 NADPH oxidase mTOR Nox4 Nox1 NADPH oxidase mTOR AMPK tuberin mTOR albumin AMPK tuberin mTOR Nox4 NADPH oxidase mTOR mTOR Nox4