Aquaporin 2 regulation: implications for water balance and polycystic kidney diseases

• Published in: Nature reviews. Nephrology 2021-11, Vol.17 (11), p.765-781
• Main Authors: Olesen, Emma T. B., Fenton, Robert A.
• Format: Article
• Language: English
• Subjects: 692/4022/1585/1; 692/4022/1585/1589; 692/4022/272/1684; A Kinase Anchor Proteins - metabolism; Antidiuretic Hormone Receptor Antagonists - therapeutic use; Aquaporin 2 - metabolism; Aquaporins; Care and treatment; Cell Membrane - metabolism; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Development and progression; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Fluconazole; Genetic aspects; Genetic regulation; Health aspects; Humans; Kidney diseases; Kidney Tubules, Collecting - metabolism; Kinases; Medicine; Medicine & Public Health; Nephrology; Phosphorylation; Polycystic kidney disease; Polycystic Kidney, Autosomal Dominant - drug therapy; Polycystic Kidney, Autosomal Dominant - metabolism; Protein Transport; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptors, Vasopressin - metabolism; Review Article; Signal Transduction; Tolvaptan - therapeutic use; Water - metabolism; Water-Electrolyte Balance - physiology; Wnt-5a Protein - metabolism
• ISSN: 1759-5061; 1759-507X
• DOI: 10.1038/s41581-021-00447-x

Targeting the collecting duct water channel aquaporin 2 (AQP2) to the plasma membrane is essential for the maintenance of mammalian water homeostasis. 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. 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. 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. 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. 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. Aquaporin 2 has an essential role in water reabsorption in the collecting duct. Here, the authors discuss novel insights in the field of aquaporin 2 regulation and how they might have implications for the treatment not only of water balance disorders but also of patients with autosomal dominant polycystic kidney disease. Key points Targeting of the collecting duct water channel aquaporin 2 (AQP2) to the plasma membrane is essential for the maintenance of mammalian water homeostasis. Although 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. 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. 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