Aquaporin-2 Inhibitors

Abstract

The critical contribution of aquaporin-2 (AQP) to water homeostasis in mammals is highlighted by the severe concentrating defects seen in humans with mutations in the AQP2 gene and in mice that are AQP2 null or have loss-of-function mutations in AQP2. 1,2 The role of the antidiuretic hormone vasopressin and its receptor, V2R, in the signaling cascade that leads to membrane accumulation of AQP2 in collecting-duct principal cells, and to an increase in renal water reabsorption, is well established. 3 The involvement of VP-induced cAMP elevation by adenylyl cyclase activation, and subsequent protein kinase A-induced phosphorylation of AQP2, is also well known. Defects in any of the major components of this signaling cascade have the potential to lead to aberrant AQP2 trafficking and function, with an associated loss of urine-concentrating ability or an inappropriate increase in collecting-duct water retention.Decreased water reabsorption leads to diabetes insipidus, either central (loss of vasopressin) or nephrogenic (loss of V2R or AQP2 function). Excessive AQP2 expression and plasma membrane localization are associated with such conditions as congestive heart failure, cirrhosis of the liver, and the syndrome of inappropriate antidiuretic hormone secretion. In such cases, inappropriate water re-absorption can lead to moderate or severe hyponatremia and its subsequent complications, sometimes fatal. Furthermore, many defects in water homeostasis result from acquired conditions, such as lithium-induced nephrogenic diabetes insipidus, a common consequence of the use of this compound as therapy for bipolar disorder.Considerable effort has therefore been expended over the past several years to identify components of the AQP2 trafficking pathway that could be targeted by drugs or other therapeutic strategies in order to alleviate the consequences of these diseases. On the basis of current knowledge of the signaling and trafficking pathways that have been elucidated by several groups, different strategies have been explored. These include bypassing the V2R-mediated signaling pathway using alternative cyclic nucleotide-generating agents, such as the cyclic guanosine monophopshate phosphodiesterase inhibitor sildenafil; 4,5 activating alternative pathways, including prostaglandin signaling; 6 and modulating trafficking with drugs, including statins, that affect the actin cytoskeleton, 7,8 a key factor in endo-and exocytotic events, as well as inhibiting endocytosis directly. 9 Some of these interventions indeed result in increased membrane AQP2 expression, and they increase urinary-concentrating ability in animal models, including vasopressin-deficient Brattleboro rats and lithium-treated rats. 2 In the current issue of JASN, Bogum et al. 10 use a smallmolecule screening approach to identify chemical compounds that inhibit cAMP-induced AQP2 membrane accumulation. Such compounds would function as aquaretics and counteract the effects of elevated vasopressin/cAMP or increased AQP2 levels in conditions that might lead to exce...

Diabetes insípida nefrogénica

“…Sin embargo, en los pacientes que reciben tratamiento prolongado con sales de litio (por ejemplo para el tratamiento de desórdenes bipolares) se han observado alteraciones en la regulación de la acuaporina-2, el canal epitelial de sodio y los transportadores de urea (UT-A1 y UT-B), con lesión y pérdida de las células principales del túbulo colector de la nefrona, lo cual puede producir una lesión irreversible del mecanismo de concentración urinaria 21,22 . Por otro lado, en los pacientes que reciben tratamientos cortos con sales de litio se puede observar recuperación completa de la alteración tubular renal 23 .…”

Computational Modeling on Aquaporin-3 as Skin Cancer Target: A Virtual Screening Study

“…There are compelling possibilities in the quest for AQPbased treatment, yet little progress has been made so far. A few reported inhibitors of AQP are appropriate for clinical trials, none of them showed any specificity for AQP3 (Niemietz and Tyerman, 2002;Migliati et al, 2009;Brown and Lu, 2013). AQP1, a close congener of AQP3 in terms of protein sequence, reported to be inhibited by tetraethylammonium salts (Brooks et al, 2000), acetazolamide (Bing et al, 2004), bumetanide (Kourghi et al, 2016), and DMSO (Vanhoek and Vanos, 1990).…”

Computational Modeling on Aquaporin-3 as Skin Cancer Target: A Virtual Screening and Molecular Dynamic Simulation Study

“…There are compelling opportunities, yet so far little progress, in the search for AQP-based therapeutics. There are a few reported AQP inhibitors suitable for clinical trials; however, none of them has shown any specificity for AQP3 [19][20][21]. AQP1, a close congener of AQP3 in terms of protein sequence, reported to be inhibited by tetraethylammonium salts [22], acetazolamide [23], bumetanide [24], and DMSO [25].…”