FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury
FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury
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FOXO3a 积累和激活加速氧化应激诱导的足细胞损伤
DOI：
10.1096/fj.202000783r
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发表时间：
2020-08-12
期刊：
影响因子：
4.8
通讯作者：
Long, Haibo
中科院分区：
文献类型：
--
作者：
Chen, Xiaowen;Liu, Wenting;Long, Haibo
足细胞损伤是糖尿病肾病肾小球损伤的主要原因。高级氧化蛋白产物(AOPPs)是糖尿病肾病氧化应激的触发因素和标志物，与足细胞损伤有关。然而，潜在的机制尚不清楚。在这里，我们研究了FOXO3a在AOPPs诱导的足细胞损伤中的潜在作用，FOXO3a是应激反应中的关键转录因子。我们发现FOXO3a在糖尿病肾病患者肾活检肾小球中的表达增加，并与蛋白尿呈正相关。糖尿病肾病患者血清中FOXO3a及其下游基因FasL和Bim显著升高，从而导致足细胞caspase3裂解水平升高，newitin和podocin表达缺失。抗晚期糖基化终产物受体(αRAGE)中和抗体阻断AOPPs信号通路可阻断糖尿病肾病血清对足细胞的作用，证实了AOPPs在糖尿病肾病血清中的致病作用。下调FOXO3a可减少AOPPs诱导的足细胞凋亡，并恢复足细胞标志物newitin和podocin的水平，上调FOXO3a则加剧了AOPPs治疗后足细胞的上述变化。此外，FOXO3a只有在AOPPs存在的情况下才能特异性地激活足细胞中的促凋亡基因。从机制上讲，AOPPs通过抑制FOXO3a蛋白的自噬降解，以ROS/mTOR依赖的方式增加FOXO3a蛋白水平。此外，AOPPs通过将FOXO3a维持在细胞核内来激活积累的FOXO3a，这一过程依赖于ROS介导的AKT信号失活。这些研究表明，FOXO3a在AOPPs诱导的糖尿病肾病足细胞损伤中起关键作用，揭示了氧化应激、FOXO3a激活和糖尿病肾病足细胞损伤之间的新的机制联系。
Podocyte injury is the primary cause of glomerular injury in diabetic nephropathy (DN). Advanced oxidation protein products (AOPPs), the triggers and markers of oxidative stress in DN, have been linked to podocyte damage. However, the underlying mechanism is not yet clear. Here, we investigated the potential role of FOXO3a, a key transcription factor in the response to stress, in mediating AOPPs-induced podocyte injury. We found that FOXO3a expression was increased in the glomeruli of kidney biopsies from patients with DN and it was positively correlated with proteinuria. The serum from patients with DN significantly increased FOXO3a and its downstream genes FasL and Bim, thereby inducing the high level of cleaved caspase3 and the loss of nephrin and podocin expressions in podocytes. Blockade of AOPPs signaling by a neutralizing antibody against the receptor of advanced glycation end products (alpha RAGE) abolished the effect of DN serum on podocytes, confirming the pathogenic role of AOPPs in DN serum. Downregulation of FOXO3a decreased AOPPs-induced podocyte apoptosis and restored the levels of podocyte markers nephrin and podocin, and upregulation of FOXO3a exacerbated these changes in podocytes after AOPPs treatment. Furthermore, FOXO3a specifically activated proapoptotic genes in podocytes only in the presence of AOPPs. Mechanistically, AOPPs increased the FOXO3a protein levels by inhibiting their autophagic degradation in a ROS/mTOR-dependent manner. Moreover AOPPs activated the accumulated FOXO3a by maintaining FOXO3a in the nucleus, and this process was dependent on ROS-mediated AKT signaling deactivation. These studies suggest that FOXO3a plays a critical role in mediating AOPPs-induced podocyte injury and reveal a new mechanistic linkage of oxidative stress, FOXO3a activation and podocyte injury in DN.