Protein UHRF1-mediated dual dysregulation of molecular chaperone GRP78 induces endoplasmic reticulum stress and aggravates diabetic nephropathy

INTRODUCTION: Endoplasmic reticulum (ER) stress mediates kidney tubular epithelial cell injury in diabetic nephropathy (DN), although the underlying regulatory mechanisms remain poorly characterized. METHODS: To examine this, human tubule epithelial cells (HK-2 cells), rat kidney tubular epithelial cells (NRK-52E cells), kidney tissues of patients with biopsy-proven DN and healthy controls along with db/db mice (spontaneous diabetic kidney injury) and their db/m littermates were subject to a variety of imaging and analytical techniques. RESULTS: Mechanistically, downregulation of protein UHRF1 induced by high glucose disrupts its regulatory functions on both promoter methylation and protein ubiquitination of GRP78. This dysregulation causes GRP78 accumulation in the cytoplasm subsequently facilitating its nuclear translocation via interactions with the nucleocytoplasmic transport machinery. Notably, GRP78 nuclear translocation enhances a gene network associated with ER stress and apoptosis, intensifying kidney tubular epithelial cell injury. Compound screening identified the phenolic glycoside Parishin as a specific inhibitor of GRP78 nuclear translocation, effectively mitigating ER stress and demonstrates kidney-protective efficacy in db/db mice. CONCLUSIONS: Overall, our findings establish the dual epigenetic regulatory mechanisms of GRP78 and demonstrate its role as a transcriptional regulator of ER stress-related gene expression, which drives tubular cells injury in DN. This suggests that targeting the nuclear translocation of GRP78 may serve as a novel therapeutic approach for DN.