Abstract
The alteration of water balance and related disorders has emerged as being strictly linked to the state of activation of the vasopressin–aquaporin-2 (vasopressin–AQP2) pathway. The lack of responsiveness of the kidney to the vasopressin action impairs its ability to concentrate the urine, resulting in polyuria, polydipsia, and risk of severe dehydration for patients. Conversely, non-osmotic release of vasopressin is associated with an increase in water permeability in the renal collecting duct, producing water retention and increasing the circulatory blood volume. This review highlights some of the new insights and recent advances in therapeutic intervention targeting the dysfunctions in the vasopressin–AQP2 pathway causing diseases characterized by water balance disorders such as congenital nephrogenic diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The recent clinical data suggest that targeting the vasopressin–AQP2 axis can provide therapeutic benefits in patients with water balance disorders.
Highlights
The maintenance of water balance is essential for all physiological processes and is critically dependent on water intake via thirst and water output in the kidney under the control of the antidiuretic hormone vasopressin
Vasopressin binds to the type 2 vasopressin receptor (V2R) and increases osmotic water transport through the regulation of the aquaporin-2 (AQP2) water channel localized in the kidney connecting tubules and collecting ducts[1,2]
This review highlights some of the new insights and recent advances in targeting the vasopressin–AQP2 pathway in some relevant diseases associated with water balance disorders, such as congenital nephrogenic diabetes insipidus (NDI), idiopathic syndrome of inappropriate antidiuretic hormone secretion (SIADH), nephrogenic syndrome of inappropriate antidiuresis (NSIAD), and autosomal dominant polycystic kidney disease (ADPKD)
Summary
The maintenance of water balance is essential for all physiological processes and is critically dependent on water intake via thirst and water output in the kidney under the control of the antidiuretic hormone vasopressin. In isolated cortical collecting ducts from a V2R-inhibited NDI mouse model, Wnt5a increased osmotic water permeability and urine osmolality, activating a different pathway of the vasopressin-induced cAMP elevation, involving a functional role of calcineurin/arachidonic acid known to induce vasopressin-like effects in mpkCCD cells. These new data point to calcineurin activators as possible drugs for the treatment of congenital NDI. Mutations in PKD1 or PKD2 are associated with a reduction in intracellular calcium, increase in cAMP, and constitutive activation of PKA, making the collecting duct principal cells under constant tonic effect of vasopressin. Co-targeting V2R and other GPCRs known to increase intracellular calcium might be a successful approach for ADPKD treatments
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