Activation of AQP2 water channels without vasopressin: therapeutic strategies for congenital nephrogenic diabetes insipidus

Abstract

Congenital nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentrating ability. Symptomatic polyuria is present from birth, even with normal release of the antidiuretic hormone vasopressin by the pituitary. Over the last two decades, the aquaporin-2 (AQP2) gene has been cloned and the molecular mechanisms of urine concentration have been gradually elucidated. Vasopressin binds to the vasopressin type II receptor (V2R) in the renal collecting ducts and then activates AQP2 phosphorylation and trafficking to increase water reabsorption from urine. Most cases of congenital NDI are caused by loss-of-function mutations to V2R, resulting in unresponsiveness to vasopressin. In this article, we provide an overview of novel therapeutic molecules of congenital NDI that can activate AQP2 by bypassing defective V2R signaling with a particular focus on the activators of the calcium and cAMP signaling pathways.

Keywords: AQP2; Calcium signaling; Congenital nephrogenic diabetes insipidus; GPCRs agonists; PDE inhibitors; cAMP signaling.

Fig. 1

The mechanisms of urine concentration by vasopressin. (Left) Circulating vasopressin binds to V2R in the basolateral membrane of cells of the renal collecting ducts. Adenylyl cyclase is then activated and increases cAMP production and PKA activity, leading to AQP2 phosphorylation. Changes in AQP2 phosphorylation status leads to translocation of cytosolic AQP2 to the apical plasma membrane. Water is reabsorbed from urine through AQP2, AQP3, and AQP4, thereby concentrating the urine. (Right) V2R mutations account for 90% of all diagnoses of congenital NDI, while AQP2 mutations occur in the other 10%. Defective V2R or AQP2 function impairs water reabsorption, resulting in urine dilution

Fig. 2

The mechanisms of urine concentration by Wnt5a. Wnt5a binds to Fzd receptors and increases intracellular calcium. The calcium-binding protein calmodulin stimulates calcineurin, which in turn, phosphorylates AQP2 and increases apical AQP2 expression. Water is then reabsorbed from urine. In addition, calcineurin increases AQP2 mRNA expression

Fig. 3

PGE2 activates AQP2 without an elevation in cAMP in mpkCCD cells. a PGE2-induced AQP2 phosphorylation at S269. PGE2 (10 nM) was added to the basolateral side of the mpkCCD cells for 1 h, as previously described [31]. b PGE2-induced AQP2 trafficking. mpkCCD cells were treated with PGE2 (10 nM) for 1 h, and the subcellular localization of AQP2 was then analyzed by immunofluorescence and confocal microscopy. The larger panels display confocal sections of the apical regions of the cells. Z-stack confocal images are shown at the top of each panel. Representative confocal images of three independent experiments are shown. Scale bars, 10 µm. c No significant elevation of cAMP concentration in response to PGE2. The mpkCCD cells were treated with PGE2 (10 nM) or [deamino-Cys1, d-Arg8]-vasopressin (dDAVP) (1 nM) for 1 h. Bars are mean values ± SD of three experiments. Asterisks indicate a significant difference as compared with the control. **p < 0.01