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

Abstract

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 GS 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.

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 GS 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 and epidermal growth factor receptor antagonists.

  • Research on the signalling networks and regulatory steps that govern AQP2 trafficking has identified promising pharmacological targets for water balance disorders.

  • 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.

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Fig. 1: Kidney aquaporins and transcellular water transport.
Fig. 2: AQP2 topology and structure.
Fig. 3: Main mechanisms underlying the regulation of AQP2 trafficking.
Fig. 4: Alternative regulators of AQP2 trafficking.
Fig. 5: Drug targets and novel treatment options for ADPKD.

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Acknowledgements

The authors’ research is supported by the Danish Medical Research Council, The Novo Nordisk Foundation, The Leducq Foundation and the Carlsberg Foundation.

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Glossary

Single effect

The difference in osmotic pressure that is created by the active transport of sodium chloride out of the tubular fluid in the thick ascending limb into the interstitium; the hyperosmotic gradient in the interstitium drives the passive movement of water from the tubular fluid of the descending limbs and collecting ducts into the interstitium.

Recycling endosomes

Organelles in the endocytic pathway, in which plasma membrane proteins and lipids that are internalized by endocytosis are sorted and processed for export back to the cell surface for reuse.

Transcytosis

The transport of macromolecular cargo from one side of a cell to the other within a membrane-bounded carrier (or carriers); this mechanism is used by multicellular organisms to selectively move material between two environments without altering their unique compositions.

Multivesicular bodies

(MVBs). Specialized endosomes that contain membrane-bound intraluminal vesicles formed by budding of the membrane into the lumen of the MVB; MVBs can fuse with lysosomes, where their contents are degraded, or they can fuse with the plasma membrane for their contents to be released into the extracellular space.

K63-linked polyubiquitin chain

A chain of ubiquitin molecules that are linked to each other on Lys63 (one of seven lysine residues within ubiquitin) to form a long polyubiquitin chain; these chains can mark the ubiquitylated protein for endocytosis.

F-actin

A filamentous polymer composed of soluble G-actin monomers; it is the most abundant component of the cytoskeleton of eukaryotes.

CFTR corrector

A family of compounds that facilitate the transport of misfolded CFTR proteins (produced owing to mutations in CFTR) to the cell membrane without being degraded.

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Olesen, E.T.B., Fenton, R.A. Aquaporin 2 regulation: implications for water balance and polycystic kidney diseases. Nat Rev Nephrol 17, 765–781 (2021). https://doi.org/10.1038/s41581-021-00447-x

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