Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow

Abstract

Glucagon-like peptide (GLP)-1 has a range of extrapancreatic effects, including renal effects. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of the present study was to localize renal GLP-1 receptors and describe GLP-1-mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and that activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using (125)I-labeled GLP-1, (125)I-labeled exendin-4 (GLP-1 analog), and (125)I-labeled exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1-mediated effects on blood pressure, renal blood flow (RBF), heart rate, renin secretion, urinary flow rate, and Na(+) and K(+) excretion were investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of (125)I-labeled GLP-1, (125)I-labeled exendin-4, and (125)I-labeled exendin 9-39 was observed in the renal vasculature, including afferent arterioles. Infusion of GLP-1 increased blood pressure, RBF, and urinary flow rate significantly in rats. Heart rate and plasma renin concentrations were unchanged. Exendin 9-39 inhibited the increase in RBF. In isolated murine kidneys, GLP-1 and exendin-4 significantly reduced the autoregulatory response of afferent arterioles in response to stepwise increases in pressure. We conclude that GLP-1 receptors are located in the renal vasculature, including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases RBF in normotensive rats.

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

“…Although GLP-1 rapidly increases atrial natriuretic factor secretion from the heart in hypertensive rats and mice (14), the majority of hypertensive subjects with diabetes treated acutely or for several weeks with GLP-1R agonists do not exhibit increased plasma levels of atrial natriuretic factor (43). Within the mouse, rat, and human kidney, the GLP-1R has been localized to a few scattered VSMs (34,45,46), and in some instances, colocalized with juxtaglomerular cells. Nevertheless, plasma renin activity is usually not altered in subjects treated with GLP-1R agonists, and there is little evidence from human studies linking sustained changes in the activity or circulating components of the renin angiotensin system with reduction in BP in hypertensive human subjects treated with GLP-1R agonists.…”

Maternal obesity and offspring risk of chronic kidney disease

“…GLP‐1 exerts glucoregulatory actions through slowing of gastric emptying and glucose‐dependent inhibition of glucagon secretion, thus improving glycaemic control. GLP‐1 receptors (GLP‐1R) are predominantly expressed in the β‐cells of the pancreas, but are also expressed in the kidneys, mainly in glomeruli and endothelial cells of the renal microvasculature, in particularly the afferent arterioles . Thus, GLP‐1R modulation may have beneficial effects in the kidney.…”

Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy

“…However, in salt-sensitive rats and hypertensive mice, GLP-1 has antihypertensive effects due to substantial diuretic and natriuretic effects (37). Moreover, in nondiabetic rodents, GLP-1 directly induces remarkable increases in renal plasma flow (RPF) and glomerular filtration rate (37) via preglomerular dilation (15).…”