MG53-mediated cell membrane repair protects against acute kidney injury
Science Translational Medicine • 18 Mar 2015 • Vol 7, Issue 279 • p. 279ra36 • DOI: 10.1126/scitranslmed.3010755
A molecular bandage for kidney injury
MG53 is a protein that is primarily expressed in muscles and helps protect muscle cells from damage. Now, Duann et al. have shown that MG53 performs a similar function in the kidney as well. The authors evaluated the role of MG53 in mouse models of kidney injury induced by ischemia and reperfusion, as well as by cisplatin, a highly nephrotoxic chemotherapy drug. In each case, recombinant MG53 could be given intravenously, and the authors found that it bound to the sites of injury on kidney cells and protected them from further damage and death. MG53 treatment did not interfere with the effectiveness of cisplatin against cancer cells, suggesting that MG53 may be useful for protecting patients’ kidneys during chemotherapy.
Abstract
Injury to the renal proximal tubular epithelium (PTE) represents the underlying consequence of acute kidney injury (AKI) after exposure to various stressors, including nephrotoxins and ischemia/reperfusion (I/R). Although the kidney has the ability to repair itself after mild injury, insufficient repair of PTE cells may trigger inflammatory and fibrotic responses, leading to chronic renal failure. We report that MG53, a member of the TRIM family of proteins, participates in repair of injured PTE cells and protects against the development of AKI. We show that MG53 translocates to acute injury sites on PTE cells and forms a repair patch. Ablation of MG53 leads to defective membrane repair. MG53-deficient mice develop pronounced tubulointerstitial injury and increased susceptibility to I/R-induced AKI compared to wild-type mice. Recombinant human MG53 (rhMG53) protein can target injury sites on PTE cells to facilitate repair after I/R injury or nephrotoxin exposure. Moreover, in animal studies, intravenous delivery of rhMG53 ameliorates cisplatin-induced AKI without affecting the tumor suppressor efficacy of cisplatin. These findings identify MG53 as a vital component of reno-protection, and targeting MG53-mediated repair of PTE cells represents a potential approach to prevention and treatment of AKI.
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Supplementary Material
Summary
Fig. S1. Ultrastructural examination of kidneys from wild-type and Mg53−/− mice.
Fig. S2. Pha-E lectin staining of primary cultured PTE cells.
Fig. S3. Recapitulation of MG53-mediated cell membrane repair in human renal proximal tubular cells.
Fig. S4. Abnormal membrane structures in Mg53−/− PTE cells.
Fig. S5. rhMG53 concentration in the PTE compartment of I/R-injured rat kidney.
Table S1. Original data and P values (provided as a separate Excel file).
Movie S1. GFP-MG53 translocation to injury sites on human HKC-8 cells.
Movie S2. GFP-C242A expressed in HKC-8 cells not responding to acute membrane injury.
Movie S3. Microelectrode penetration into PTE cells derived from wild-type mice.
Movie S4. Microelectrode penetration into PTE cells derived from Mg53−/− mice.
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Published In
Science Translational Medicine
Volume 7 | Issue 279
March 2015
March 2015
Copyright
Copyright © 2015, American Association for the Advancement of Science.
Submission history
Received: 24 September 2014
Accepted: 3 February 2015
Acknowledgments
We thank the excellent service from Novoprotein Scientific Inc. for providing the scale-up production of rhMG53 protein used in this study and appreciate L. Racusen for providing the HKC-8 cells. We acknowledge the support from the Pathology Core and CMIF Core at The Ohio State University. We also thank R. Cianciolo for help with the KIM-1 IHC studies and H. Ma for reading of the manuscript. Funding: This work was supported by NIH grants AR061385, HL069000, and AG028614 to J.M.; U54 CA163111 to T.L.; HL084583, HL083422, and HL114383 to P.J.M.; and U01 DK096927 to B.R. H.Z. was the recipient of an American Heart Association Scientist Development grant. Author contributions: P.D., H.L., B.R., P.J.M., W.T.A., and J.M. developed the concept for the studies. P.D. and H.L. performed I/R- and cisplatin-induced AKI models, tumor allograft animal studies, endogenous MG53 and exogenous rhMG53 characterization, and specimen collections. P.L., T.T., X.Z., K.G., and B.R. performed urinary analyses and biochemical studies. Z.W., K.C., H.Z., and C.Z. performed in vitro cell imaging and toxicological studies of rhMG53. T.L. established KPC-Brca1 tumor cell lines. J.M. oversaw the entire project. P.D., B.R., P.J.M., and J.M. wrote the manuscript, and all authors contributed to revision of the manuscript. Competing interests: J.M. has an equity interest in TRIM-edicine, which develops rhMG53 for treatment of human diseases. Patents on the use of MG53 are held by Rutgers University–Robert Wood Johnson Medical School.
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