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IGFBP2 induces podocyte apoptosis promoted by mitochondrial damage via integrin α5/FAK in diabetic kidney disease

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Abstract

Podocyte apoptosis or loss is the pivotal pathological characteristic of diabetic kidney disease (DKD). Insulin-like growth factor-binding protein 2 (IGFBP2) have a proinflammatory and proapoptotic effect on diseases. Previous studies have shown that serum IGFBP2 level significantly increased in DKD patients, but the precise mechanisms remain unclear. Here, we found that IGFBP2 levels obviously increased under a diabetic state and high glucose stimuli. Deficiency of IGFBP2 attenuated the urine protein, renal pathological injury and glomeruli hypertrophy of DKD mice induced by STZ, and knockdown or deletion of IGFBP2 alleviated podocytes apoptosis induced by high concentration of glucose or in DKD mouse. Furthermore, IGFBP2 facilitated apoptosis, which was characterized by increase in inflammation and oxidative stress, by binding with integrin α5 (ITGA5) of podocytes, and then activating the phosphorylation of focal adhesion kinase (FAK)-mediated mitochondrial injury, including membrane potential decreasing, ROS production increasing. Moreover, ITGA5 knockdown or FAK inhibition attenuated the podocyte apoptosis caused by high glucose or IGFBP2 overexpression. Taken together, these findings unveiled the insight mechanism that IGFBP2 increased podocyte apoptosis by mitochondrial injury via ITGA5/FAK phosphorylation pathway in DKD progression, and provided the potential therapeutic strategies for diabetic kidney disease.

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Funding

This work was supported by grants from National Key Research and Development Program of China (2018YFE0126600), National Natural Science Foundation of China (No. 82070741 and 82270758).

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  1. Xiaochen Wang, Yifan Zhang, and Kun Chi contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China

    Xiaochen Wang, Yifan Zhang, Kun Chi, Yuwei Ji, Keying Zhang, Ping Li, Zhangning Fu, Xu Wang, Shaoyuan Cui, Wanjun Shen, Guangyan Cai, Xiangmei Chen, Hanyu Zhu & Quan Hong

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  1. Xiaochen Wang
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  2. Yifan Zhang
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Contributions

QH and HZ supervised the project, designed, edited, and led out the experiments of this study. GYC and XMC revised the manuscript. XCW and YFZ drafted the manuscript. XCW performed most of the experiments and analyzed the data. YFZ, KC and YWJ performed experimentation on IGFBP2null mouse and analyzed the data. KYZ and ZNF provided support with experiments and mouse breeding. PL, XW, SYC and provided technical guidance with cell and biological experiments. WJS performed transmission electron microscope analysis.

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Correspondence to Hanyu Zhu or Quan Hong.

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Wang, X., Zhang, Y., Chi, K. et al. IGFBP2 induces podocyte apoptosis promoted by mitochondrial damage via integrin α5/FAK in diabetic kidney disease. Apoptosis 29, 1109–1125 (2024). https://doi.org/10.1007/s10495-024-01974-1

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