Vasopressin regulates the renin-angiotensin-aldosterone system via V1a receptors in macula densa cells

1 Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo; 2 Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, and 3 Department of Pharmacy, Kumamoto University Hospital, Kumamoto; and 4 Department of Physiology, Kitasato University School of Medicine, Kanagawa, Japan Submitted 19 February 2008 ; accepted in final form 28 April 2008 The neuropeptide hormone arginine-vasopressin (AVP) is well known to exert its antidiuretic effect via the vasopressin V2 receptor (V2R), whereas the role of the vasopressin V1a receptor (V1aR) in the kidney remains to be clarified. Previously, we reported decreased plasma volume and blood pressure in V1a receptor-deficient (V1aR –/– ) mice (Koshimizu T, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T. Proc Natl Acad Sci USA 103: 7807–7812, 2006). In this study, we investigated the role of V1aR in urine concentration, renal function, and the renin-angiotensin system (RAS) using V1aR –/– mice. Urine volume of V1aR –/– mice was greater than that of wild-type mice, particularly when water was loaded, while the glomerular filtration rate (GFR), urinary NaCl excretion, AVP-dependent cAMP generation, V2R, and aquaporin 2 (AQP2) expression in the kidney were lower, indicating that the diminished GFR and V2R-AQP2 system led to impaired urinary concentration in V1aR –/– mice. Since the GFR and V2R-AQP2 system are regulated by RAS, we analyzed renin and angiotensin II in V1aR –/– mice and found that the plasma renin and angiotensin II were decreased. The expression of renin in granule cells was decreased in V1aR –/– mice, which led to a decreased level of plasma renin. In addition, the expression of renin stimulators such as neuronal nitric oxide synthase and cyclooxygenase-2 in macula densa (MD) cells, where V1aR was specifically expressed, was decreased in V1aR –/– mice. These data indicate that AVP regulates body fluid homeostasis and GFR via the V1aR in MD cells by activating RAS and subsequently the V2R-AQP2 system. renin-angiotensin system Address for reprint requests and other correspondence: H. Nonoguchi, Div. of Kidney and Dialysis, Dept. of Internal Medicine, Hygo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan (e-mail: nono{at}hyo-med.ac.jp )