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Abstract: FR-PO218

The Mechanism of Mfn2 Regulating ABCG1-Mediated Cholesterol Efflux in Glomerular Endothelial Cells of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Yin, Qinghua, West China Hospital of Sichuan University, Chengdu, SiChuan, China
  • Fu, Ping, West China Hospital of Sichuan University, Chengdu, SiChuan, China
  • Ma, Liang, Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan Univeristy, Chengdu, China
Background

Diabetic kidney disease (DKD), is one of the most common microvascular complications of diabetes mellitus. Increasing evidence has shown that renal lipotoxicity plays an important role in the pathogenesis of DKD .The ATP-binding cassette transporter (ABC) G1 mediates intracellular cholesterol efflux. It has been found that overexpression of mitochondrial fusion protein 2 (Mfn2) in macrophages promotes ABCG1-mediated cholesterol efflux. In this study, we investigated the mechanism of Mfn2 regulating ABCG1-mediated cholesterol efflux in glomerular endothelial cell of diabetic kidney disease.

Methods

Glomerular endothelial cell specific knockout ABCG1 (ABCG1-GEC KO) mice and C57BL/6J (WT-N) mice were induced to type 2 diabetes. Another mice in each group were injected with Ad-Mfn2 adenovirus to establish diabetes model. After 8 weeks, mice were sacrificed and collected peripheral blood for detecting creatinine, lipids and glycosylated hemoglobin (HbA1c),and cholesterol efflux and mitochondrial function were detected.The kidney cortex tissue was taken freshly to extract the expression of ABCG1, inflammatory factors. In vitro, adenoviro-induced overexpression of Mfn2 and ABCG1 in glomerular endothelial cells were cultrued with high glucose to clearfy the relationship between Mfn2 and ABCG1. Specific inhibitors of PPAR-γ and PPAR-β were used to reveal the relationship of Mfn2 and ABCG1.

Results

In vivo experiments, cholesterol content increased significantly and mitochondrial respiratory was dysfunction obviously. Immunohistochemical demonstrated that the expression of inflammatory factors increased, while the expression of ABCG1 and Mfn2 decreased. The oxidative phosphorylation (OXPHOS) of kidney mitochondria complex I/II (CI/CII) and electron transfer ability (ETS) decreased significantly in experimental group (P <0.05) . In vitro experiments, the mitochondrial function regulated by Mfn2. The expression of ABCG1 was reduced and cholesterol efflux was blocked by specific inhibitors of PPAR-γand PPAR-β compared with control group.

Conclusion

Mfn2 mediated mitochondrial dysfunction plays an important role in cholesterol homeostasis incued by ABCG1 deficiency. In diabetic kidney disease, overexpression of Mfn2 could relieve the renal damage caused by cholesterol accumulation, which increased the expression of ABCG1 depending on PPAR-γ/PPAR-β.