GLP-1-induced renal vasodilation in rodents depends exclusively on the known GLP-1 receptor and is lost in prehypertensive rats.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.

Glucagon-like peptide-1 receptors in the kidney: impact on renal autoregulation.

Glucagon-like peptide-1 (GLP-1) and strategies based on this blood sugar-reducing and appetite-suppressing hormone are used to treat obesity and type 2 diabetes. However, the GLP-1 receptor (GLP-1R) is also present in the kidney, where it influences renal function. The effect of GLP-1 on the kidney varies between humans and rodents. The effect of GLP-1 on kidney function also seems to vary depending on its concentration and the physiological or pathological state of the kidney. In studies with rodents or humans, acute infusion of pharmacological doses of GLP-1 stimulates natriuresis and diuresis. However, the effect on the renal vasculature is less clear. In rodents, GLP-1 infusion increases renal plasma flow and glomerular filtration rate, suggesting renal vasodilation. In humans, only a subset of the study participants exhibits increased renal plasma flow and glomerular filtration rate. Differential status of kidney function and changes in renal vascular resistance of the preglomerular arterioles may account for the different responses of the human study participants. Because renal function in patients with type 2 diabetes is already at risk or compromised, understanding the effects of GLP-1R activation on kidney function in these patients is particularly important. This review examines the distribution of GLP-1R in the kidney and the effects elicited by GLP-1 or GLP-1R agonists. By integrating results from acute and chronic studies in healthy individuals and patients with type 2 diabetes along with those from rodent studies, we provide insight into how GLP-1R activation affects renal function and autoregulation.