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GLP-1RA improves diabetic renal injury by alleviating glomerular endothelial cells pyrotosis via
Weixi Wu1,2, Yao Wang1,2, Xian Shao1,2
1NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
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.
Insights
High glucose in diabetic kidney disease causes cell damage via cholesterol buildup. GLP-1 receptor agonists protect kidneys by regulating the RXRα/circ8411/miR-23a-5p/ABCA1 pathway, offering a potential therapeutic strategy.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic kidney disease (DKD) is linked to lipotoxicity, but the impact of high glucose and the kidney-protective effects of GLP-1 receptor agonists (GLP-1RAs) are not fully understood.
- Investigating the mechanisms of high glucose-induced renal injury and the role of GLP-1RAs is crucial for DKD management.
Purpose of the Study:
- To elucidate the role of cholesterol accumulation and pyroptosis in glomerular endothelial cells (GEnCs) under high glucose conditions.
- To determine the renal protective mechanisms of GLP-1 receptor agonists (GLP-1RAs) in DKD.
Main Methods:
- Utilized RT-qPCR, Oil Red O staining, Western blotting, and LDH assays to assess cholesterol and pyroptosis.
- Employed circRNA microarrays, bioinformatics, and functional experiments to identify regulatory pathways.
- Conducted in vivo studies using C57BL/6J and ApoE-deficient mice to validate findings.
Main Results:
- High glucose reduced cholesterol efflux and ABCA1 expression, leading to cholesterol accumulation and pyroptosis in GEnCs.
- Identified circ8411 as a suppressor of miR-23a-5p, inhibiting ABCA1, with high glucose downregulating circ8411 via RXRα inhibition.
- GLP-1RAs mitigated cholesterol accumulation and pyroptosis by modulating the RXRα/circ8411/miR-23a-5p/ABCA1 pathway, with beneficial effects observed in diabetic mice.
Conclusions:
- The RXRα/circ8411/miR-23a-5p/ABCA1 pathway mediates high glucose-induced lipotoxic renal injury in DKD.
- Targeting this pathway presents a potential therapeutic strategy for DKD and hypercholesterolemia.
- GLP-1RAs exert renal protection by activating this identified pathway.
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