Collège de France, Neuropeptides Centraux et Régulations Hydrique et Cardiovasculaire, Centre Interdisciplinaire de Recherche en Biologie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Paris, France.
Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France.
Am J Physiol Renal Physiol. 2021 Sep 1;321(3):F305-F321. doi: 10.1152/ajprenal.00081.2021. Epub 2021 Jul 20.
Although vasopressin V receptor (VR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V agonist d[Leu, Lys]VP, either fluorescent or radioactive, we showed that VR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of VR were very low compared with the V receptor (VR). On the microdissected IMCD, d[Leu, Lys]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca concentration increase mobilization with an EC value in the nanomolar range. This effect involved both intracellular Ca mobilization and extracellular Ca influx. The selective V antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca concentration but also cAMP, suggesting a cooperation between VR and VR in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V agonist triggered significant diuretic effects, in contrast with injection of selective V agonist. This study brings new data on the localization and signaling pathways of VR in the kidney, highlights a cross talk between VR and VR in the IMCD, and suggests that VR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by VR activation. Although VR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of VR, highlights a cross talk between VR and V receptor (VR) in the inner medullary collecting duct, and suggests that VR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by VR activation.
虽然已在肾脏中检测到血管加压素 V 受体 (VR) mRNA，但该受体的确切肾脏定位以及药理学和生理学特性仍不清楚。本研究使用选择性 V 激动剂 d[Leu, Lys]VP（荧光或放射性），结果表明 VR 主要存在于雄性大鼠肾脏的内髓集合管 (IMCD) 的主细胞中。与 V 受体 (VR) 相比，VR 的蛋白和 mRNA 表达水平非常低。在微分离的 IMCD 上，d[Leu, Lys]VP 对 cAMP 产生没有影响，但诱导剂量依赖性和饱和细胞内 Ca 浓度增加，动员 EC 值在纳摩尔范围内。这种作用涉及细胞内 Ca 动员和细胞外 Ca 内流。选择性 V 拮抗剂 SSR149415 强烈降低了血管加压素增加细胞内 Ca 浓度的能力，但也降低了 cAMP，这表明在表达两种受体的 IMCD 细胞中，VR 和 VR 之间存在协同作用。这种协同作用源于涉及蛋白激酶 C 的第二信使级联的串扰，而不是受体异二聚体化，因为在共表达两种受体同工型的人胚肾 293 细胞中，增强了精氨酸血管加压素刺激的 cAMP 产生，并且生物发光共振能量转移实验得到了阴性结果，这支持了这一观点。在体内，只有急性给予高剂量的 V 激动剂才能引发明显的利尿作用，而选择性 V 激动剂则相反。这项研究提供了关于 VR 在肾脏中的定位和信号通路的新数据，突出了在 IMCD 中 VR 和 VR 之间的串扰，并表明在某些病理生理条件下，VR 可能会抵消 VR 激活引发的抗利尿作用。虽然已在肾脏中检测到血管加压素 V 受体 (VR) mRNA，但该受体的确切肾脏定位以及药理学和生理学特性仍不清楚。本研究使用原创药物工具，提供了关于 VR 定位和信号通路的新数据，突出了在肾脏内髓集合管中 VR 和 V 受体 (VR) 之间的串扰，并表明在某些病理生理条件下，VR 可能会抵消 VR 激活引发的抗利尿作用。
