Insufficient repair of proximal tubular epithelium (PTE) cells following acute kidney injury (AKI) can result in inflammatory and fibrotic responses, which may progress to chronic renal failure. Now, Duann et al. show that MG53 — a TRIM family protein involved in the cell-membrane-repair machinery — mediates membrane repair in PTE cells and protects against AKI-induced damage. MG53-deficient mice exhibited exacerbated kidney damage following ischaemia–reperfusion (I–R) AKI, whereas recombinant MG53 protected rats against I–R-induced damage. Intravenous delivery of recombinant MG53 also ameliorated the effects of cisplatin-induced AKI without affecting antitumour activity.