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GDF11, a target of miR-32-5p, suppresses high-glucose-induced mitochondrial dysfunction and apoptosis in HK-2 cells through PI3K/AKT signaling activation

  • Nephrology - Original Paper
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Abstract

Purpose

To investigate the role and underlying mechanism of GDF11 on diabetic nephropathy (DN)-related mitochondrial dysfunction and apoptosis.

Methods

A DN model of rats was established in this study. Human Kidney-2 (HK-2) cells were cultured under high-glucose (HG) condition with or without recombinant GDF11 (rGDF11). Mitochondrial morphology of HK-2 cells was analyzed by transmission electron microscope and MitoTracker Red CMXRos staining. Mitochondrial membrane potential (MMP) and ROS production were monitored using JC-1 assay kit and MitoSOX staining, respectively. Cell apoptosis was detected by TUNEL or flow cytometry assays.

Results

Herein, we observed that GDF11 was down-regulated in renal cortex and serum of DN rats, which was accompanied by renal mitochondrial morphological abnormalities. In line with the findings in vivo, HK-2 cells exposed to HG presented with mitochondrial morphological alterations and further apoptosis accompanied by GDF11 reduction. In addition, HG promoted a decrease in MMP while an increase in mitochondrial ROS production. Conversely, rGDF11 treatment significantly alleviated these HG-induced mitochondrial defects in HK-2 cells. Meanwhile, HK-2 cell apoptosis induced by HG was simultaneously suppressed by rGDF11. Mechanistically, the decreased levels of p-AKT induced by HG were attenuated after rGDF11 administration. Inhibition of the PI3K/AKT pathway resisted the effects of rGDF11 on the MMP and apoptosis of HK-2 cells. In addition, we identified that GDF11 is a target of miR-32-5p. Up-regulation of miR-32-5p could inhibit the expression of GDF11.

Conclusion

rGDF11 treatment rescued HG-induced HK-2 cell mitochondrial dysfunction and apoptosis, which may be dependent on the activation of the PI3K/AKT pathway.

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Data availability

All data generated or used during the study appear in the submitted article.

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Acknowledgements

This work was supported by the Natural Science Foundation of Heilongjiang Province (Grant No. LH2020H064)

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Author notes

  1. Hongjie Wang and Yunxia Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Street, Harbin, China

    Hongjie Wang & Huan Liu

  2. Department of Endocrinology, Da Qing Long Nan Hospital, Daqing, China

    Yunxia Zhang

  3. Harbin Medical University, Harbin, China

    Shuang Li

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  1. Hongjie Wang
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Correspondence to Hongjie Wang.

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This study was approved by the Experimental Animal Ethics Committee of The Fourth Affiliated Hospital of Harbin Medical University. We have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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11255_2023_3495_MOESM1_ESM.tif

Supplementary file1 Fig. S1 (A) Quantification of MitoTracker Red CMXRos staining in Fig. 2F: the ratio of HK-2 cells with fragmented mitochondria. (B-C) Quantification of JC-1 (shown in Fig. 2G) and Mito SOX staining (shown in Fig. 2H), respectively (TIF 387 KB)

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Wang, H., Zhang, Y., Liu, H. et al. GDF11, a target of miR-32-5p, suppresses high-glucose-induced mitochondrial dysfunction and apoptosis in HK-2 cells through PI3K/AKT signaling activation. Int Urol Nephrol 55, 1767–1778 (2023). https://doi.org/10.1007/s11255-023-03495-3

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