FOXO3a accumulation and activation accelerate oxidative stress‐induced podocyte injury
Autor: | Jing Xiao, Xiaowen Chen, Congwei Luo, Shuting Li, Wangqiu Gong, Wenting Liu, Yuxian Wang, Ying Zhang, Fenfen Peng, Na Wu, Xiaoyang He, Yanxia Liu, Haibo Long, Qianyin Huang, Yiyi Zhuang, Yihua Chen |
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Rok vydání: | 2020 |
Předmět: |
Glycation End Products
Advanced 0301 basic medicine Receptor for Advanced Glycation End Products Apoptosis medicine.disease_cause Biochemistry Podocyte Diabetic nephropathy Nephrin Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Glycation Autophagy Genetics medicine Animals Humans Diabetic Nephropathies Molecular Biology Protein kinase B biology Podocytes Chemistry Forkhead Box Protein O3 Intracellular Signaling Peptides and Proteins Membrane Proteins medicine.disease Cell biology Mice Inbred C57BL Oxidative Stress 030104 developmental biology medicine.anatomical_structure Advanced Oxidation Protein Products Podocin biology.protein Biomarkers 030217 neurology & neurosurgery Oxidative stress Biotechnology |
Zdroj: | The FASEB Journal. 34:13300-13316 |
ISSN: | 1530-6860 0892-6638 |
Popis: | 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 (αRAGE) 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. |
Databáze: | OpenAIRE |
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