A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus

Abstract

X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE 2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology. These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI.

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus

“…These patients do not respond to VP (or dDAVP), and at present there is no specific treatment for this condition. Possible therapeutic strategies may involve activation of the cGMP pathway (17), the use of pharmacological chaperones (18), or, as recently proposed, stimulation of the EP4 receptor (19). In the present studies, we demonstrate that direct stimulation of the E-prostanoid receptor, EP2, could be an alternative mechanism to increase kidney concentrating ability.…”

“…Recently, a specific agonist for the EP4 receptor (ONO-AE1-329) increased kidney concentrating abilities in a mouse model of NDI (19). We determined that an alternative EP4 receptor specific agonist (CAY10580) induced acute targeting of AQP2 to the membrane in MDCK cells, providing a molecular mechanism for the previously reported effects.…”

“…Although the functional role of this phosphorylation site is not known in detail, ser-264 is not essential for AQP2 trafficking (2) but may determine the fate of AQP2 following endocytic retrieval and thereby protein half-life (26). Thus, the previously described effect of an EP4 agonist on AQP2 protein abundance (19) hypothetically could be the result of either stimulation of AQP2 gene transcription or decreased AQP2 degradation.…”

“…Butaprost markedly decreased urine flow rate and increased urine osmolality in these rats, indicating that pharmacological stimulation of the EP2 receptor may be a suitable future target for the treatment of NDI. In particular, an EP2 receptor agonist in combination with EP4 receptor stimulation, which has previously been shown to relieve NDI symptoms in a mouse model of NDI (19), may have major therapeutic potential. Therapeutically, pharmacological stimulation of the EP2 receptor, rather than the EP4 receptor, could have advantages.…”

Urinary concentration: different ways to open and close the tap

“…Indeed, rats treated with a blocker of Avpr2 develop a pharmacologically induced NDI and the phenotype could be significantly alleviated by treatment with an EP2 agonist [33]. Similarly, the NDI in mice deleted for the Avpr2 gene could be ameliorated by selective EP4 agonists [34]. Diagnostic difficulties can also arise in those patients with milder mutations, that retain some functionality of AVPR2; so-called partial NDI [35].…”