BACKGROUND

Lipotoxicity has been implicated in diabetic kidney disease (DKD). However, the role of high glucose levels in DKD and the underlying renal protective mechanisms of GLP-1 receptor agonists (GLP-1RAs) remain unclear.

METHODS

To investigate cholesterol accumulation, pyroptosis in glomerular endothelial cells (GEnCs), and the renal protective mechanisms of GLP-1RAs, we used various techniques, including RT-qPCR, Oil Red O staining, Western blotting, lactate dehydrogenase (LDH) activity assays, circRNA microarrays, bioinformatics analysis, gain and loss-of-function experiments, rescue experiments, and luciferase assays. Additionally, in vivo experiments were conducted using C57BL/6J and ApoE-deficient (ApoE-/-) mice.

RESULTS

GEnCs exposed to high glucose exhibited reduced cholesterol efflux, which was accompanied by downregulation of ATP-binding cassette transporter A1 (ABCA1) expression, cholesterol accumulation, and pyroptosis. Circ8411 was identified as a regulator of ABCA1, inhibiting miR-23a-5p through its binding to the 3'UTR. Additionally, higher glucose levels decreased circ8411 expression by inhibiting RXRα. GLP-1RAs effectively reduced cholesterol accumulation and cell pyroptosis by targeting the RXRα/circ8411/miR-23a-5p/ABCA1 pathway. In diabetic ApoE-/- mice, renal structure and function were impaired, with resulted in increased cholesterol accumulation and pyroptosis; however, GLP-1RAs treatment reversed these detrimental changes.

CONCLUSIONS

These findings suggest that the RXRα/circ8411/miR-23a-5p/ABCA1 pathway mediates the contribution of high glucose to lipotoxic renal injury. Targeting this pathway may represent a potential therapeutic strategy for patients with DKD and hypercholesterolemia. Moreover, GLP-1RAs may provide renal protective effects by activating this pathway.