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J Biol Chem. 2016 Dec 16;291(51):26487-26501. Epub 2016 Oct 26.

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

Author information

1
From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and.
2
the Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
3
From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and liufangfh@163.com.

Abstract

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 knock-out (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 up-regulating ABCA1. In human glomerular endothelial cells, GLP-1R-mediated signaling pathways (e.g. Ca2+/calmodulin-dependent protein kinase, cAMP/PKA, PI3K/AKT, and 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.

KEYWORDS:

ABC transporter; apolipoprotein E (ApoE); cholesterol efflux; cholesterol metabolism; cholesterol regulation; diabetic kidney disease; diabetic nephropathy; exendin-4; glomerular endothelial cell

PMID:
27784780
PMCID:
PMC5159509
DOI:
10.1074/jbc.M116.730564
[Indexed for MEDLINE]
Free PMC Article

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