Abstract
Mitsugumin 53 (MG53) is a tripartite motif family protein that has been reported to attenuate injury via membrane repair in different organs. Contrast-induced acute kidney injury (CI-AKI) is a common complication caused by the administration of iodinated contrast media (CM). While the cytotoxicity induced by CM leading to tubular cell death may be initiated by cell membrane damage, we wondered whether MG53 alleviates CI-AKI. This study was designed to investigate the effect of MG53 on CI-AKI and the underlying mechanism. A rat model of CI-AKI was established, and CI-AKI induced the translocation of MG53 from serum to injury sites on the renal proximal tubular (RPT) epithelia, as illustrated by immunoblot analysis and immunohistochemical staining. Moreover, pretreatment of rats with recombinant human MG53 protein (rhMG53, 2 mg/mL) alleviated iopromide-induced injury in the kidney, which was determined by measuring serum creatinine, blood urea nitrogen and renal histological changes. In vitro studies demonstrated that exposure of RPT cells to iopromide (20, 40, and 80 mg/mL) caused cell membrane injury and cell death, which were attenuated by rhMG53 (10 and 50 μg/mL). Mechanistically, MG53 translocated to the injury site on RPT cells and bound to phosphatidylserine to protect RPT cells from iopromide-induced injury. In conclusion, MG53 protects against CI-AKI through cell membrane repair and reducing cell apoptosis; therefore, rhMG53 might be a potential effective means to treat or prevent CI-AKI.
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Acknowledgements
These studies were supported in part by grants to CZ from the National Key R&D Program of China (2018YFC1312700), National Natural Science Foundation of China (31730043, 81600585), Program of Innovative Research Team by National Natural Science Foundation of China (81721001), Chongqing Technology Innovation and Application Demonstration Project (cstc2018jscx-mszdX0024), and Clinical Medical Research Personnel Training Program of the Army Medical University (2018XLC10I2). Research conducted in the laboratories of JJM and BHR was supported by the US National Institutes of Health (R01-DK106394).
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CYZ, YH, and CL designed the experiments. CL, YHH, YBW, YZ, XQZ, DFH, HMR, YKL, PHL, and HCL performed the experiments and analyzed the data. CL, YHH, and HYW prepared the original manuscript. TT, BHR, JJM, and CYZ revised the manuscript.
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JJM and TT have an equity interest in TRIM-edicine, Inc., which develops rhMG53 for the treatment of human diseases. Patents on the use of MG53 are held by Rutgers University—Robert Wood Johnson Medical School.
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Liu, C., Hu, Yh., Han, Y. et al. MG53 protects against contrast-induced acute kidney injury by reducing cell membrane damage and apoptosis. Acta Pharmacol Sin 41, 1457–1464 (2020). https://doi.org/10.1038/s41401-020-0420-8
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DOI: https://doi.org/10.1038/s41401-020-0420-8
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