F1000Research 2019, 8(F1000 Faculty Rev):149 Last updated: 17 JUL 2019 REVIEW Vasopressin–aquaporin-2 pathway: recent advances in understanding water balance disorders [version 1; peer review: 3 approved] Marianna Ranieri 1, Annarita Di Mise1, Grazia Tamma1,2, Giovanna Valenti 1-3 1Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy, 70125, Italy 2Istituto Nazionale di Biostrutture e Biosistemi, Rome, Roma, Italy, 00136, Italy 3Center of Excellence in Comparative Genomics (CEGBA), University of Bari, Bari, Italy, 70125, Italy First published: 04 Feb 2019, 8(F1000 Faculty Rev):149 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.16654.1) Latest published: 04 Feb 2019, 8(F1000 Faculty Rev):149 ( https://doi.org/10.12688/f1000research.16654.1) Reviewer Status Abstract Invited Reviewers The alteration of water balance and related disorders has emerged as 1 2 3 being strictly linked to the state of activation of the vasopressin–aquaporin-2 (vasopressin–AQP2) pathway. The lack of responsiveness of the kidney to version 1 the vasopressin action impairs its ability to concentrate the urine, resulting published in polyuria, polydipsia, and risk of severe dehydration for patients. 04 Feb 2019 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 F1000 Faculty Reviews are written by members of highlights some of the new insights and recent advances in therapeutic the prestigious F1000 Faculty. They are intervention targeting the dysfunctions in the vasopressin–AQP2 pathway commissioned and are peer reviewed before causing diseases characterized by water balance disorders such as publication to ensure that the final, published version congenital nephrogenic diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, nephrogenic syndrome of inappropriate is comprehensive and accessible. The reviewers antidiuresis, and autosomal dominant polycystic kidney disease. The recent who approved the final version are listed with their clinical data suggest that targeting the vasopressin–AQP2 axis can provide names and affiliations. therapeutic benefits in patients with water balance disorders. Keywords 1 Enno Klussmann, Max Delbrück Center for Vasopressin, AQP2, NDI, SIADH, NSIAD, ADPKD Molecular Medicine Berlin (MDC), Berlin, Germany 2 Kenichi Ishibashi, Meiji Pharmaceutical University, Tokyo, Japan 3 Tae-Hwan Kwon, Kyungpook National University, Taegu, South Korea Any comments on the article can be found at the end of the article. Page 1 of 11 F1000Research 2019, 8(F1000 Faculty Rev):149 Last updated: 17 JUL 2019 Corresponding author: Giovanna Valenti ([email protected]) Author roles: Ranieri M: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Di Mise A: Writing – Original Draft Preparation; Tamma G: Writing – Original Draft Preparation; Valenti G: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: No competing interests were disclosed. Grant information: This study was supported in part by Telethon funding (grant number GGP13227) and by ASI (Italian Space Agency, grant number 2013-091-R.0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2019 Ranieri M et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Ranieri M, Di Mise A, Tamma G and Valenti G. Vasopressin–aquaporin-2 pathway: recent advances in understanding water balance disorders [version 1; peer review: 3 approved] F1000Research 2019, 8(F1000 Faculty Rev):149 ( https://doi.org/10.12688/f1000research.16654.1) First published: 04 Feb 2019, 8(F1000 Faculty Rev):149 (https://doi.org/10.12688/f1000research.16654.1) Page 2 of 11 F1000Research 2019, 8(F1000 Faculty Rev):149 Last updated: 17 JUL 2019 Introduction Vasopressin–AQP2 pathway in water balance disorders The maintenance of water balance is essential for all physio- Plasma copeptin as a surrogate marker of vasopressin logical processes and is critically dependent on water intake via secretion in renal disorders thirst and water output in the kidney under the control of the Significant progress in studying the role of vasopressin in renal antidiuretic hormone vasopressin. An increase in plasma osmo- disorders came from the identification of copeptin, a stable sur- lality, sensed by osmoreceptors situated in the brain, represents rogate marker of vasopressin secretion that is relatively easily the most important input to cause thirst and stimulation of vaso- measured30–33. Copeptin is a peptide corresponding to the COOH- pressin release. Vasopressin is secreted into the circulation by the terminal portion of pro-vasopressin and is co-secreted in equimo- posterior pituitary gland in response to an increase in serum osmo- lar amounts with vasopressin, representing a good biomarker for lality or a decrease in blood volume. In the kidney, vasopressin vasopressin34. Indeed, it has been reported that plasma con- binds to the type 2 vasopressin receptor (V2R) and increases centrations of copeptin correlate strongly in several clinical osmotic water transport through the regulation of the aquaporin-2 conditions32,33,35,36. In a large cross-sectional study, plasma (AQP2) water channel localized in the kidney connecting tubules copeptin and microalbuminuria positively correlated37, and this and collecting ducts1,2. V2R is a G-protein-coupled receptor correlation was also found to persist with a 16-year follow-up38. (GPCR) localized at the basolateral plasma membrane of the prin- The increase in urinary albumin excretion is likely to reflect not cipal cells of the kidney collecting duct. A recent transcriptome only glomerular damage but also systemic endothelial dysfunc- study of 14 microdissected nephron segments of rat kidney dem- tion and is consistent with the hypothesis that vasopressin induces onstrated the V2R mRNA expression from the medullary thick urinary albumin excretion as previously reported in rats and ascending limb to the inner medullary collecting duct3. Upon bind- humans39,40. Conversely, suppressing vasopressin by administer- ing of vasopressin to V2R, a Gs protein is activated, leading to ing a V2R antagonist or by simply increasing water intake might stimulation of adenylyl cyclases, increase in intracellular cAMP, be beneficial for renal function and diabetes39,41. and activation of protein kinase A (PKA). The cAMP/PKA signal transduction cascade results in multiple phosphorylating events As shown previously, vasopressin levels are also increased in in the C-terminus of the water channel AQP2 regulating its diabetic nephropathy characterized by dysregulation of water bal- trafficking and the water luminal permeability2,4–6. Vasopressin ance displaying water depletion as a consequence of osmotic diu- also triggers increases in intracellular calcium required for AQP2 resis due to glycosuria42, probably to limit water loss. Of interest, trafficking7,8. in patients with type 2 diabetes, plasma copeptin was found to be associated with a faster decline in glomerular filtration rate Most of the effect of vasopressin is thought to be related to PKA- (GFR) in two distinct studies43,44. mediated phosphorylation currently explored by large-scale phosphoproteomics to identify regulated proteins’ downstream The role of vasopressin is particularly central in the pathogenesis PKA activation9. On the other hand, several proteins participat- of another severe disease, ADPKD, characterized by the expan- ing in the control of cAMP-dependent AQP2 trafficking, including sion of renal cysts eventually leading to loss of renal function. SNAREs, annexin-2, hsc70, A-kinase anchoring proteins (AKAPs), Association of urinary copeptin with the severity of ADPKD was and small GTPases of the Rho family proteins controlling cytoskel- also recently demonstrated44, suggesting that copeptin can repre- etal dynamics, have been identified10–18. In addition to phosphor- sent a novel marker to predict renal prognosis in ADPKD. Copep- ylation, AQP2 undergoes different regulated post-translational tin levels are negatively associated with GFR, kidney size, and modifications, such as ubiquitination and glutathionylation, number of renal cysts33,45,46. While ADPKD is the most advanced which are likely to be fundamental for controlling AQP2 cellular disease for the therapeutic use of vasopressin receptor blockade, localization, stability, and function19–23. this strategy is also currently being explored in chronic kidney diseases (CKDs). Besides short-term regulation of AQP2 trafficking, vasopressin regulates the total amount of the water channel within the cell and In summary, the vasopressin–AQP2 system has a critical role in alters the protein half-life of AQP224–29. Alterations in AQP2 abun- various stages of CKD47–49 and in several kidney diseases46, mak- dance as well as defects in vasopressin signaling in the renal col- ing this pathway very promising from a therapeutic perspective. lecting duct can