KEY POINTS

-acetylgalactosaminyltransferase-3 (GALNT3) was downregulated in both ischemic AKI and cisplatin nephrotoxicity. GALNT3 played a protective role in renal tubular cells, and its downregulation contributed to AKI. Mechanistically, GALNT3 protected kidney tubular cells at least partially through O-glycosylation of EGF receptor.

BACKGROUND

Damages to subcellular organelles, such as mitochondria and endoplasmic reticulum, are well recognized in tubular cell injury and death in AKI. However, the changes and involvement of Golgi apparatus are much less known. In this study, we report the regulation and role of -acetylgalactosaminyltransferase-3 (GALNT3), a key enzyme for protein glycosylation in Golgi apparatus, in AKI.

METHODS

AKI was induced in mice by renal ischemia–reperfusion injury or cisplatin. , 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. EGF receptor (EGFR) activation was induced by recombinant EGF or by overexpressing EGFR.

RESULTS

GALNT3 was significantly decreased in both and models of AKI induced by renal ischemia–reperfusion injury 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, whereas overexpression of GALNT3 attenuated H/R-induced apoptosis, further supporting a protective role of GALNT3. Mechanistically, GALNT3 contributed to O-glycosylation of EGFR and associated EGFR signaling. Activation or overexpression of EGFR suppressed the proapoptotic 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.