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

Matthias Hautmann^*, Ulla G. Friis, Michael Desch^*, Vladimir Todorov^*, Hayo Castrop^*, Florian Segerer^*, Christiane Otto, Günther Schütz and Frank Schweda^*

^* Institute of Physiology, University of Regensburg, Regensburg, Germany; Department of Physiology and Pharmacology, University of Southern Denmark, Odense C, Denmark; and Division of Molecular Biology of the Cell, German Cancer Research Center, Heidelberg, Germany

Address correspondence to: Dr. Frank Schweda, Institute for Physiology, University of Regensburg, 93040 Regensburg, Germany. Phone: +49-941-9432957; Fax: +49-941-9434315; E-mail: frank.schweda{at}klinik.uni-regensburg.de

Received for publication June 19, 2006. Accepted for publication February 1, 2007.

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 low- or 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673