GALNT3 in Ischemia-Reperfusion Injury of the Kidney

Background: Damages to subcellular organelles, such as mitochondria and endoplasmic reticulum, are well-recognized in tubular cell injury and death in acute kidney injury (AKI). However, the changes and involvement of Golgi apparatus are much less known. Here, we report the regulation and role of N-acetylgalactosaminyltransferase-3 (GALNT3), a key enzyme for protein glycosylation in Golgi apparatus, in AKI. Methods: AKI was induced in mice by renal ischemia-reperfusion or cisplatin. In vitro, rat kidney proximal tubular cells were subjected to hypoxia/reoxygenation (H/R) injury. To determine the role of GALNT3, its specific inhibitor T3inh-1 was tested in mice, and the effects of GALNT3 overexpression as well as knockdown were examined in the rat renal proximal tubular cells. EGFR activation was induced by recombinant EGF or by overexpressing EGFR. Results: GALNT3 was significantly decreased in both in vivo and in vitro models of AKI induced by renal ischemia-reperfusion and cisplatin. T3Inh-1, a specific GALNT3 inhibitor, exacerbated ischemic AKI and suppressed tubular cell proliferation in mice. Moreover, knockdown of GALNT3 increased apoptosis during H/R treatment in rat renal proximal tubular cells, while overexpression of GALNT3 attenuated H/R-induced apoptosis, further supporting a protective role of GALNT3. Mechanistically, GALNT3 contributed to O-glycosylation of epidermal growth factor receptor (EGFR) and associated EGFR signalling. Activation or overexpression of EGFR suppressed the pro-apoptotic effect of GALNT3 knockdown in H/R-treated rat renal proximal tubular cells. Conclusions: GALNT3 protected kidney tubular cells in AKI at least partially through O-glycosylation of EGFR.