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.
Highlights
ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney
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
SiRNA-mediated knockdown of CaM Kinase Type IV (CaMKIV) suppressed the increased effect of ABCA1 mRNA and protein levels induced by exendin-4 (Fig. 5, E and F), whereas ABCA1 expression increased in cells transfected with scrambled siRNA. These findings demonstrate the involvement of CaM kinase kinase (CaMKK)/CaMKIV signaling in exendin-4-induced ABCA1 expression
Summary
ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney. We found significantly decreased ABCA1 expression in glomerular endothelial cells of diabetic apoE؊/؊ mice and increased renal lipid, cholesterol, and inflammatory cytokine levels. 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. Glucagon-like peptide-1 receptor (GLP-1R), which is expressed in kidney tissue [16], and its agonists [17] exert potential renoprotective effects in DKD by decreasing oxidative stress, lipid accumulation, macrophage infiltration, and proinflammatory cytokine release while improving metabolic abnormalities. In this study we investigated the effects of the GLP-1R agonist exendin-4 on renal lipotoxicity-induced glomerular endothelial cell inflammatory injury and ABCA1-mediated cholesterol efflux in diabetic apoEϪ/Ϫ mice and in human renal glomerular endothelial cells (HRGEC)
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