Vasopressin (AVP) and its receptors play a pivotal role in maintaining body homeostasis under physiological and pathophysiological conditions. As a consequence, the vasopressin system has emerged as an important target for both diagnostic and therapeutic applications in a number of medical conditions. Stoichiometric generation of AVP with copeptin, which is relatively accessible in the blood for measurements, makes copeptin a valuable surrogate of AVP. In this review, we present the regulation of release of AVP and activation of V1a, V1b, and V2 vasopressin receptors under physiological and pathological conditions. We make a survey of the role of AVP in: the regulation of the cardiovascular system; body fluid osmolality; natraemia; endocrine regulation; food intake; metabolism; circadian rhythmicity, immunological processes; and in the formation of learning, memory, cognition, and emotional and social behaviours. We also discuss the significance of the inappropriate functioning of the vasopressin system for: the development of cardiovascular diseases; disturbances of the water-electrolyte balance; energy metabolism; inflammatory processes; pain; neurogenic stress; memory disorders; depression; anxiety; autism; and schizophrenia. The structure and biological properties of peptide and non-peptide agonists and antagonists of V1a, V1b and V2 vasopressin receptors are presented and the potential use of copeptin and the current and likely indications for AVP agonists and antagonists in the diagnosis and therapeutics of multiple pathological conditions is discussed.

Background: Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway.Methods: We correlated the NRP1, 2 levels to patients’ survival using online available data base. Human and mouse ccRCC cells were knocked-out for theNRP1andNRP2genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs.Results: Knock-out of theNRP1andNRP2genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients.Conclusions: Our study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.