O‐Glycosylation of E‐Cadherin Induced by Endoplasmic Reticulum Stress Negatively Regulates Cell Polarity and Proliferation in Acute Kidney Injury

ABSTRACT

The loss of polarity and cell cycle arrest of renal tubular epithelial cells (RTECs) represent important mechanisms of acute kidney injury (AKI). Endoplasmic reticulum stress (ER stress) often occurs in the kidneys during AKI, regulating protein translation and post‐translational modification. E‐cadherin, a key regulator of cell polarity, undergoes O‐glycosylated during ER stress. However, the role of E‐cadherin O‐glycosylation in kidney injury and repair remains to be elucidated. Cisplatin (CP)/lipopolysaccharide (LPS)‐induced AKI mouse models and cell models were established to evaluate ER stress in the RTECs. The glycan modification and localization of E‐cadherin, as well as its interaction with β‐catenin, were evaluated in vitro through Western blot, immunoprecipitation, and immunofluorescence. Small molecular inhibitors targeting ER stress (4‐PBA) or O‐glycosylation (OSMI‐1) were utilized to investigate the effects on E‐cadherin O‐glycosylation, RTECs polarity and proliferation in vivo and in vitro. Both CP‐ and LPS‐induced AKI triggered ER stress in RTECs, which led to O‑glycosylation of E‑cadherin, loss of cell polarity, and impaired proliferation. Notably, removal of a brief ER stress pulse allowed RTECs to regain normal polarity and proliferation, indicating the reversibility of this process. Consistently, pharmacological inhibition of ER stress or O‑glycosylation effectively restored these phenotypes in vitro. Moreover, in vivo suppression of ER stress in CP‑induced AKI mice significantly recovered renal function and promoted tubular cell proliferation. Together, these results establish ER stress‑driven E‑cadherin O‑glycosylation as a critical upstream event in AKI‑associated tubular repair failure and suggest that targeting this axis holds therapeutic promise. These findings establish ER stress‐driven E‐cadherin O‐glycosylation as a critical upstream mechanism of tubular repair failure in AKI, and suggest that targeting this axis represents a promising therapeutic strategy for restoring renal function.