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Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice.

Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice.
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Yin QH, Zhang R, Li L, Wang YT, Liu JP, Zhang J, Bai L, Cheng JQ, Fu P, Liu F,


Yin QH, Zhang R, Li L, Wang YT, Liu JP, Zhang J, Bai L, Cheng JQ, Fu P, Liu F, (click to view)

Yin QH, Zhang R, Li L, Wang YT, Liu JP, Zhang J, Bai L, Cheng JQ, Fu P, Liu F,

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The Journal of biological chemistry 2016 Oct 26() pii jbc.M116.730564
Abstract

The ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney. Research has shown that exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, promotes ABCA1 expression in multiple tissues and organs; however, the mechanisms underlying exendin-4 induction of ABCA1 expression in glomerular endothelial cells are not fully understood. In this study we investigated the effect of exendin-4 on ABCA1 in glomerular endothelial cells of diabetic kidney disease (DKD) and the possible mechanism. We observed a marked increase in glomerular lipid deposits in tissues of patients with DKD and diabetic apolipoprotein E knockout (apoE-/-) mice by Oil Red O staining and biochemical analysis of cholesterol. We found significantly decreased ABCA1 expression in glomerular endothelial cells of diabetic apoE-/- mice and increased renal lipid, cholesterol, and inflammatory cytokine levels. Exendin-4 decreased renal cholesterol accumulation and inflammation and increased cholesterol efflux by upregulating ABCA1. In human glomerular endothelial cells (HRGECs), GLP-1R-mediated signaling pathways (e.g., Ca2+/calmodulin-dependent protein kinase, cAMP/protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2) were involved in cholesterol efflux and inflammatory responses by regulating ABCA1 expression. We propose that exendin-4 increases ABCA1 expression in glomerular endothelial cells, which plays an important role in alleviating renal lipid accumulation, inflammation, and proteinuria in mice with type 2 diabetes.

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