Renoprotective mechanisms of glucagon-like peptide-1 receptor agonists

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, secreted from gut endocrine cells, which acts to potentiate nutrient-induced insulin secretion. Activation of its receptor, GLP-1R, decreases glucagon secretion and gastric emptying, thereby decreasing blood glucose and body weight. It is largely through these mechanisms that Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the treatment of type 2 diabetes. More recently, preclinical and clinical studies have reported that these agents have potent extra-pancreatic effects, exhibiting cardioprotective and renoprotective actions. The recent FLOW trial was the first multicentre clinical trial investigating the effect of GLP-1RAs on a primary renal outcome and reported robust evidence that GLP-1RAs are renoprotective. Studies in rodent models of renal injury have shown that gain and loss of GLP-1R signalling improves or deteriorates kidney function. However, the precise mechanisms responsible for renal benefits of GLP-1RAs are not yet fully understood. While prolonged activation of GLP-1 receptors (GLP-1R) has been shown to reverse diabetes-related disruptions in gene expression across various renal cell populations, GLP-1R expression in both rodent and human kidneys is thought to be primarily confined to certain vascular smooth muscle cells. This review discusses recent advances in our understanding of the effects of GLP-1 medicines on the kidney with a focus on indirect and direct mechanisms of action.