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: Qing-Hua Yin, Rui Zhang, Li Li, Yi-Ting Wang, Jing-Ping Liu, Jie Zhang, Lin Bai, Jing-Qiu Cheng, Ping Fu, Fang Liu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 51 Pg. 26487-26501 (Dec 16 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27784780 (Publication Type: Journal Article)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ABCA1 protein, mouse
• ATP Binding Cassette Transporter 1
• Apolipoproteins E
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Peptides
• Venoms
• Cholesterol
• Exenatide
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Cyclic AMP-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 3

Topics

• ATP Binding Cassette Transporter 1 (genetics, metabolism)
• Animals
• Apolipoproteins E (deficiency, metabolism)
• Cholesterol (genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Diabetes Mellitus, Experimental (drug therapy, genetics, metabolism)
• Diabetic Nephropathies (drug therapy, genetics, metabolism)
• Endothelial Cells (metabolism, pathology)
• Exenatide
• Female
• Glucagon-Like Peptide-1 Receptor (genetics, metabolism)
• Humans
• Kidney Glomerulus (metabolism, pathology)
• MAP Kinase Signaling System (drug effects, genetics)
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Peptides (pharmacology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proteinuria (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Venoms (pharmacology)