Pituitary Adenylate Cyclase–Activating Polypeptide Stimulates Renin Secretion via Activation of PAC1 Receptors

Abstract

Besides of its functional role in the nervous system, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of cardiovascular function. Therefore, PACAP is a potent vasodilator in several vascular beds, including the renal vasculature. Because the kidney expresses both PACAP and PACAP-binding sites, it was speculated that PACAP might regulate cardiovascular function by direct vascular effects and indirectly by regulating renin release from the kidneys. PACAP (1-27) stimulated renin secretion from isolated perfused kidneys of rats 4.9-fold with a half-maximum concentration of 1.9 nmol/L. In addition, PACAP stimulated renin release and enhanced membrane capacitance of isolated juxtaglomerular cells, indicating a direct stimulation of exocytotic events. The effect of PACAP on renin release was mediated by the specific PACAP receptors (PAC1), because PACAP (1-27) applied in concentrations in the physiologic range (10 and 100 pmol/L) did not enhance renin release from isolated kidneys of PAC1 receptor knockout mice (PAC1؊/؊), whereas it stimulated renin release 1.38-and 2.5-fold in kidneys from wild-type mice. Moreover, plasma renin concentration was significantly lower in PAC1؊/؊ compared with their wild-type littermates under control conditions as well as under a lowor high-salt diet and under treatment with the angiotensin-converting enzyme inhibitor ramipril, whereas no differences in plasma renin concentration between the genotypes were detectable after water deprivation. These data show that PACAP acting on PAC1 receptors potently stimulates renin release, serving as a tonic enhancer of the renin system in vivo.

Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat

“…The different PACAP receptors have had specific actions demonstrated in several systems. The PAC1 receptor is important in renin secretion (21) and PACAP-induced depolarizations in superior cervical ganglion neurons (1). The VPAC1 receptor, on the other hand, is necessary for pressureinduced vasodilatation (11), and evidence from our present study suggests that it may be primarily involved in the MAP response observed after intrathecal infusion of PACAP-38.…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…It has been suggested that vasopressin release in response to acute dehydration is mediated through activation of PACAP receptors by endogenous PACAP released within the rat supraoptic nucleus (Gillard et al, 2006), and PACAP has been shown to stimulate renin secretion via activation of PAC1-R (Hautmann et al, 2007). These observations show that PACAP plays a role in the regulation of drinking behavior and body fluid balance after water deprivation.…”

Physiology of Kidney Renin

“…Plasma renin activity (PRA) is measured as the generation of ANG I without the addition of exogenous renin substrate.] In addition to catecholamines, other hormones, such as the prostaglandins E 2 and I 2 (prostacyclin) (402), dopamine (476), calcitonin gene-related peptide (482), pituitary adenylyl cyclase activating polypeptide (PACAP) (322), and adrenomedullin (397), stimulate the renin release from isolated JG cells and increase the intracellular cAMP concentrations.…”