title: Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice.
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.
authors: From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and.
authors: Qing-Hua
authors: QH
authors: Yin
authors: From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and.
authors: Rui
authors: R
authors: Zhang
authors: From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and.
authors: Li
authors: L
authors: Li
authors: From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and.
authors: Yi-Ting
authors: YT
authors: Wang
authors: 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.
authors: Jing-Ping
authors: JP
authors: Liu
authors: 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.
authors: Jie
authors: J
authors: Zhang
authors: 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.
authors: Lin
authors: L
authors: Bai
authors: 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.
authors: Jing-Qiu
authors: JQ
authors: Cheng
authors: From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and.
authors: Ping
authors: P
authors: Fu
authors: From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and liufangfh@163.com.
authors: Fang
authors: F
authors: Liu
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002784:Cholesterol; D017868:Cyclic AMP-Dependent Protein Kinases; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D048052:Mitogen-Activated Protein Kinase 3; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014688:Venoms; C577833:Abca1 protein, mouse; C000593834:Glp1r protein, mouse
keywords: ABC transporter; apolipoprotein E (ApoE); cholesterol efflux; cholesterol metabolism; cholesterol regulation; diabetic kidney disease; diabetic nephropathy; exendin-4; glomerular endothelial cell