Decreased expression of the GLP-1 receptor after segmental artery injury in mice.

Abstract

The glucagon-like peptide-1 receptor (GLP1R) is expressed in the renal vasculature and known to be downregulated under hypertensive conditions in rats and humans. However, little is known about the regulation in other types of renal pathology involving vascular changes. This study investigates the expression of the GLP1R in renal vasculature after glomerular injury in the nephrotoxic nephritis mouse model, high cholesterol, and atherosclerosis in the Ldlr-/- mouse on Western diet, and ex vivo injury in an organ culture model. The immunohistochemical signal of the GLP1R was significantly decreased in arteries from mice with nephrotoxic nephritis after 42 days compared to 7 days and saline control (P < 0.05). Histological evaluation of kidneys from Ldlr-/- mice on Western diet showed a decreased GLP1R specific immunohistochemical signal (P < 0.05). The dilatory response to liraglutide was decreased in Western diet fed Ldlr-/- mice compared to C57Bl/6J controls (P < 0.05). Organ culture significantly decreased the immunohistochemical signal of the GLP1R (P <0.05) and the expression of Glp1r mRNA (P < 0.005) compared to fresh. Organ cultured vessels showed vascular smooth muscle cell remodelling as Acta2 expression was decreased (P < 0.005) and Ednrb was increased (P < 0.05). In conclusion, nephrotoxic nephritis and hypercholesterolaemia led to decreased GLP1R specific immunohistochemical signal. Ex vivo vascular injury in the organ culture model leads to a decrease in expression of GLP1R expressionand contractile VSMC specific markers and increase in expression of dedifferentiation markers suggestive of an inverse relationship between phenotypic switch of the VSMC and the expression of the GLP1R; however, the causal relationship remains elusive.