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mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes
Stéphanie Eid1,2, Suzan Boutary1, Kawthar Braych1
11 Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut , Beirut, Lebanon .
Aim:
Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. We explored the hypothesis that mammalian target of rapamycin complex 2 (mTORC2) mediates podocyte injury in diabetes.
Results:
High glucose (HG)-induced podocyte injury reflected by alterations in the slit diaphragm protein podocin and podocyte depletion/apoptosis. This was paralleled by activation of the Rictor/mTORC2/Akt pathway. HG also increased the levels of Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using small interfering RNA (siRNA)-targeting Rictor in vitro decreased HG-induced Nox1 and Nox4, NADPH oxidase activity, restored podocin levels, and reduced podocyte depletion/apoptosis. Inhibition of mTORC2 had no effect on mammalian target of rapamycin complex 1 (mTORC1) activation, described by our group to be increased in diabetes, suggesting that the mTORC2 activation by HG could mediate podocyte injury independently of mTORC1. In isolated glomeruli of OVE26 mice, there was a similar activation of the Rictor/mTORC2/Akt signaling pathway with increase in Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using antisense oligonucleotides targeting Rictor restored podocin levels, reduced podocyte depletion/apoptosis, and attenuated glomerular injury and albuminuria.
Innovation:
Our data provide evidence for a novel function of mTORC2 in NADPH oxidase-derived reactive oxygen species generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes.
Conclusion:
mTORC2 and/or NADPH oxidase inhibition may represent a therapeutic modality for diabetic kidney disease. Antioxid. Redox Signal. 25, 703-719.
Insights
Mammalian target of rapamycin complex 2 (mTORC2) activation contributes to diabetic kidney disease by increasing oxidative stress and podocyte apoptosis. Inhibiting mTORC2 may offer a therapeutic strategy for diabetic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Diabetology
Background:
- Podocyte apoptosis is a key factor in albuminuria and kidney fibrosis.
- Oxidative stress from hyperglycemia significantly contributes to glomerular injury in diabetes.
Purpose of the Study:
- To investigate the role of mammalian target of rapamycin complex 2 (mTORC2) in mediating podocyte injury during diabetes.
- To explore the link between mTORC2, oxidative stress, and podocyte apoptosis in diabetic kidney disease.
Main Methods:
- Utilized in vitro cell culture with high glucose conditions and in vivo studies using OVE26 mice.
- Employed small interfering RNA (siRNA) and antisense oligonucleotides to inhibit mTORC2 via Rictor.
- Assessed podocin levels, podocyte apoptosis, NADPH oxidase activity, and albuminuria.
Main Results:
- High glucose activated the Rictor/mTORC2/Akt pathway, increasing Nox4 and NADPH oxidase activity, leading to podocyte injury.
- mTORC2 inhibition reduced oxidative stress, restored podocin, and decreased podocyte apoptosis and albuminuria.
- mTORC2 inhibition did not affect mTORC1 activation, suggesting an independent role in diabetic kidney injury.
Conclusions:
- mTORC2 plays a significant role in generating reactive oxygen species via NADPH oxidase, promoting podocyte apoptosis in type 1 diabetes.
- Targeting mTORC2 or NADPH oxidase presents a potential therapeutic approach for managing diabetic kidney disease.
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