ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease

Background: Hyperglycemia and dyslipidemia are two major characteristics of diabetes. In this study, the effects of glomerular cholesterol accumulation primarily due to ABCA1 deficiency on glomerular endothelial injury in diabetic kidney disease (DKD) and the possible mechanisms were investigated. Methods: The effects of ABCA1 deficiency on glomerular lipid deposition and kidney injury were examined in a type 2 diabetic mouse model with ABCA1 deficiency in glomerular endothelial cells (DM-ABCA1-/- mice) and human renal glomerular endothelial cells (HRGECs) cultured in high glucose and high cholesterol conditions, which simulated type 2 diabetes in vitro. Results: ABCA1 deficiency in glomerular endothelial cells exacerbated renal lipid deposition and kidney injuries in type 2 diabetic mice and manifested as increased creatinine levels, more severe proteinuria, mesangial matrix expansion and fusion of foot processes, and more pronounced renal inflammatory injury and cell death. In HRGECs cultured under high glucose and high cholesterol conditions, ABCA1 deficiency increased the deposition of cellular cholesterol, contributed to inflammation and apoptosis, damaged the endothelial glycocalyx barrier, and induced endoplasmic reticulum stress (ERS). Conversely, ABCA1 overexpression enhancing cholesterol efflux or inhibition of ERS in vitro, significantly protected against glomerular endothelial injury stimulated by high glucose and high cholesterol. Conclusions: These findings establish a pathogenic role of ABCA1 deficiency in glomerular endothelium injury and dysfunction and imply that ABCA1 may represent a potential effective therapeutic target for early diabetic kidney disease.