Eid Stéphanie, Boutary Suzan, Braych Kawthar, Sabra Ramzi, Massaad Charbel, Hamdy Ahmed, Rashid Awad, Moodad Sarah, Block Karen, Gorin Yves, Abboud Hanna E, Eid Assaad A
1 Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut , Beirut, Lebanon .
2 UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cite University , Centre Interdisciplinaire Chimie Biology, Paris, France .
Antioxid Redox Signal. 2016 Nov 1;25(13):703-719. doi: 10.1089/ars.2015.6562. Epub 2016 Sep 12.
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.
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.
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.
mTORC2 and/or NADPH oxidase inhibition may represent a therapeutic modality for diabetic kidney disease. Antioxid. Redox Signal. 25, 703-719.
足细胞凋亡是导致尿白蛋白过度丢失并最终引发肾纤维化的关键机制。氧化应激在高血糖诱导的肾小球损伤中起关键作用。我们探讨了雷帕霉素复合物2（mTORC2）介导糖尿病中足细胞损伤的假说。
高糖（HG）诱导的足细胞损伤表现为裂孔隔膜蛋白足动蛋白的改变以及足细胞耗竭/凋亡。这与Rictor/mTORC2/Akt信号通路的激活平行。HG还增加了Nox4水平和NADPH氧化酶活性。在体外使用靶向Rictor的小干扰RNA（siRNA）抑制mTORC2可降低HG诱导的Nox1和Nox4、NADPH氧化酶活性，恢复足动蛋白水平，并减少足细胞耗竭/凋亡。抑制mTORC2对雷帕霉素复合物1（mTORC1）的激活没有影响，我们的研究小组曾描述mTORC1在糖尿病中会增加，这表明HG激活mTORC2可独立于mTORC1介导足细胞损伤。在OVE26小鼠的分离肾小球中，Rictor/mTORC2/Akt信号通路有类似的激活，同时Nox4和NADPH氧化酶活性增加。使用靶向Rictor的反义寡核苷酸抑制mTORC2可恢复足动蛋白水平，减少足细胞耗竭/凋亡，并减轻肾小球损伤和蛋白尿。
我们的数据为mTORC2在NADPH氧化酶衍生的活性氧生成和足细胞凋亡中的新功能提供了证据，这有助于1型糖尿病患者的尿白蛋白排泄。
抑制mTORC2和/或NADPH氧化酶可能是治疗糖尿病肾病的一种方法。《抗氧化与氧化还原信号》25卷，703 - 719页。
