Aoyagi Toshinori, Izumi Yuichiro, Hiroyama Masami, Matsuzaki Takanobu, Yasuoka Yukiko, Sanbe Atsushi, Miyazaki Hiroki, Fujiwara Yoko, Nakayama Yushi, Kohda Yukimasa, Yamauchi Junji, Inoue Takeaki, Kawahara Katsumasa, Saito Hideyuki, Tomita Kimio, Nonoguchi Hiroshi, Tanoue Akito
Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Am J Physiol Renal Physiol. 2008 Jul;295(1):F100-7. doi: 10.1152/ajprenal.00088.2008. Epub 2008 Apr 30.
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.
神经肽激素精氨酸加压素（AVP）通过加压素V2受体（V2R）发挥其抗利尿作用是众所周知的，而加压素V1a受体（V1aR）在肾脏中的作用仍有待阐明。此前，我们报道了V1a受体缺陷（V1aR-/-）小鼠的血浆容量和血压降低（小清水哲、那佐洋、田上明、及川辽、川原洋、清野洋、安达哲、田中哲、桑木哲、森哲。《美国国家科学院院刊》103:7807 - 7812,2006）。在本研究中，我们使用V1aR-/-小鼠研究了V1aR在尿液浓缩、肾功能和肾素-血管紧张素系统（RAS）中的作用。V1aR-/-小鼠的尿量大于野生型小鼠，尤其是在饮水负荷时，而肾小球滤过率（GFR）、尿NaCl排泄、AVP依赖性cAMP生成、V2R以及肾脏中水通道蛋白2（AQP2）的表达较低，这表明GFR和V2R - AQP2系统的减弱导致V1aR-/-小鼠尿液浓缩功能受损。由于GFR和V2R - AQP2系统受RAS调节，我们分析了V1aR-/-小鼠中的肾素和血管紧张素II，发现血浆肾素和血管紧张素II降低。V1aR-/-小鼠颗粒细胞中的肾素表达降低，这导致血浆肾素水平降低。此外，在特异性表达V1aR的致密斑（MD）细胞中，肾素刺激因子如神经元型一氧化氮合酶和环氧化酶-2的表达在V1aR-/-小鼠中降低。这些数据表明，AVP通过激活RAS并随后激活V2R - AQP2系统，经由MD细胞中的V1aR调节体液平衡和GFR。
