Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC. A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus.
Familial hypothalamic diabetes insipidus in rats. Tolvaptan in later-stage autosomal dominant polycystic kidney disease.
#Cytoscape pathway flux trial#
Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Tolvaptan in patients with autosomal dominant polycystic kidney disease. Acquired forms of central diabetes insipidus: Mechanisms of disease. Targeting the trafficking of kidney water channels for therapeutic benefit. Renal aquaporins and water balance disorders. Mouse models and the urinary concentrating mechanism in the new millennium. Physiological roles of AQP7 in the kidney: lessons from AQP7 knockout mice. Mammalian urine concentration: a review of renal medullary architecture and membrane transporters. Investigating plasma membrane targeting of AQP2 using agents that do not increase cellular proliferation and epithelial secretion is required to delineate the independent role of AQP2 in cyst progression in autosomal dominant polycystic kidney disease. Research on the signalling networks and regulatory steps that govern AQP2 trafficking has identified promising pharmacological targets for water balance disorders. Novel regulators of AQP2 plasma membrane targeting that are independent of V2R and cAMP include A-kinase anchoring protein (AKAP)–PKA disruptors, Src inhibition, Wnt5a, fluconazole and epidermal growth factor receptor antagonists. The canonical V2R signalling pathway - increased cAMP levels, activation of protein kinase A (PKA) and AQP2 phosphorylation - cannot fully explain AQP2 plasma membrane targeting, and cAMP–PKA-independent pathways exist. Targeting of the collecting duct water channel aquaporin 2 (AQP2) to the plasma membrane is essential for the maintenance of mammalian water homeostasis.Īlthough vasopressin signalling via the G S protein-coupled vasopressin V2 receptor (V2R) is a major receptor-mediated pathway that modulates trafficking of AQP2 to the plasma membrane, this targeting can also occur independently of V2R. Here, we highlight advances in the field of AQP2 regulation that might be exploited for the treatment of water balance disorders and provide a rationale for targeting these pathways in autosomal dominant polycystic kidney disease. Notably, several regulatory processes and signalling pathways involved in AQP2 trafficking also have a role in the pathophysiology of autosomal dominant polycystic kidney disease, although the role of AQP2 in cyst progression is unknown. In addition, although AQP2 phosphorylation is a known prerequisite for V2R-mediated plasma membrane targeting, none of the known AQP2 phosphorylation events appears to be rate-limiting in this process, which suggests the involvement of other factors cytoskeletal remodelling has also been implicated. Although a rise in cAMP levels and activation of protein kinase A are involved in facilitating the actions of V2R, studies in knockout mice and cell models have suggested that cAMP signalling pathways are not an absolute requirement for V2R-mediated AQP2 trafficking to the plasma membrane. The vasopressin V2 receptor (V2R), which is a G S protein-coupled receptor that increases intracellular cAMP levels, has a major role in this targeting process. Targeting the collecting duct water channel aquaporin 2 (AQP2) to the plasma membrane is essential for the maintenance of mammalian water homeostasis.
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