Lixivaptan, a New Generation Diuretic, Counteracts Vasopressin-Induced Aquaporin-2 Trafficking and Function in Renal Collecting Duct Cells.

Annarita Di Mise,Maria Venneri,Lorenzo Pellegrini,Giovanna Valenti,Marianna Ranieri,Mariangela Centrone,Grazia Tamma

doi:10.3390/ijms21010183

Abstract

Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic drug would be preferable over a conventional diuretic. The clinical efficacy of vaptans is in principle due to impaired vasopressin-regulated water reabsorption via the water channel aquaporin-2 (AQP2). Here, the effect of lixivaptan—a novel selective V2R antagonist—on the vasopressin-cAMP/PKA signaling cascade was investigated in mouse renal collecting duct cells expressing AQP2 (MCD4) and the human V2R. Compared to tolvaptan—a selective V2R antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia—lixivaptan has been predicted to be less likely to cause liver injury. In MCD4 cells, clinically relevant concentrations of lixivaptan (100 nM for 1 h) prevented dDAVP-induced increase of cytosolic cAMP levels and AQP2 phosphorylation at ser-256. Consistent with this finding, real-time fluorescence kinetic measurements demonstrated that lixivaptan prevented dDAVP-induced increase in osmotic water permeability. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of lixivaptan and suggest that lixivaptan has the potential to become a safe and effective therapy for the treatment of disorders characterized by high plasma vasopressin concentrations and water retention.

Highlights

Vaptans are non-peptide and orally active vasopressin receptor antagonists which act both on Vasopressin V1a Receptor (V1aR) and V2 receptor (V2R) or selectively on V2R
In 2009, tolvaptan—a specific V2R antagonist—was approved by the Food and Drug Administration (FDA) for the treatment of euvolemic and hypervolemic hyponatremia associated with heart failure, cirrhosis, and SIADH [7,8,9]
Since vasopressin binding to V2R is associated with an increase in intracellular cAMP levels, the effect of lixivaptan on cAMP levels was investigated with fluorescence resonance energy transfer (FRET)-based EPAC biosensors, as previously described [15]

Summary

Introduction

Vaptans are non-peptide and orally active vasopressin receptor antagonists which act both on Vasopressin V1a Receptor (V1aR) and V2R or selectively on V2R. Vasopressin binds V2R receptor and activates the cAMP signal transduction pathway, which in turn results in the transport of AQP2-containing vesicles to the apical plasma membrane and consequent water reabsorption [1,2,3]. Tolvaptan is the first drug approved by regulatory authorities in Japan, Europe, Canada, and the USA for the treatment of ADPKD (autosomal dominant polycystic kidney disease) in patients at high risk of progression to ESRD (end stage renal disease). Tolvaptan was shown to delay the rate of decline in renal function in ADPKD patients, presumably by inhibiting intracellular cAMP production in the kidney and slowing the rate of renal volume increase [10,11]. The therapeutic benefit of tolvaptan has been widely reported, treatment with tolvaptan has been associated with important adverse effects, including polyuria and potentially severe liver injury [10,11]

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Results

Conclusion