The Role of Vasopressin V2 Receptor in Drug-Induced Hyponatremia

Hyponatremia is frequently encountered in clinical practice and usually induced by renal water retention. Many medications are considered to be among the various causes of hyponatremia, because they either stimulate the release of arginine vasopressin (AVP) or potentiate its action in the kidney. Antidepressants, anticonvulsants, antipsychotics, diuretics, and cytotoxic agents are the major causes of drug-induced hyponatremia. However, studies addressing the potential of these drugs to increase AVP release from the posterior pituitary gland or enhance urine concentration through intrarenal mechanisms are lacking. We previously showed that in the absence of AVP, sertraline, carbamazepine, haloperidol, and cyclophosphamide each increased vasopressin V2 receptor (V2R) mRNA and aquaporin-2 (AQP2) protein and mRNA expression in primary cultured inner medullary collecting duct cells. The upregulation of AQP2 was blocked by the V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors. These findings led us to conclude that the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the main mechanism of drug-induced hyponatremia. Previous studies have also shown that the V2R has a role in chlorpropamide-induced hyponatremia. Several other agents, including metformin and statins, have been found to induce antidiuresis and AQP2 upregulation through various V2R-independent pathways in animal experiments but are not associated with hyponatremia despite being frequently used clinically. In brief, drug-induced hyponatremia can be largely explained by AQP2 upregulation from V2R-cAMP-PKA signaling in the absence of AVP stimulation. This paper reviews the central and nephrogenic mechanisms of drug-induced hyponatremia and discusses the importance of the canonical pathway of AQP2 upregulation in drug-induced NSIAD.

Updates and Perspectives on Aquaporin-2 and Water Balance Disorders

Ensuring the proper amount of water inside the body is essential for survival. One of the key factors in the maintenance of body water balance is water reabsorption in the collecting ducts of the kidney, a process that is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and impermeable to ions or other small molecules. Impairments of AQP2 result in various water balance disorders, including nephrogenic diabetes insipidus (NDI), which is a disease characterized by a massive loss of water through the kidney and consequent severe dehydration. Dysregulation of AQP2 is also a cause of water retention with hyponatremia in heart failure, hepatic cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone vasopressin is an upstream regulator of AQP2. Its binding to the vasopressin V2 receptor promotes AQP2 targeting to the apical membrane and thus enables water reabsorption. Tolvaptan, a vasopressin V2 receptor antagonist, is effective and widely used for water retention with hyponatremia. However, there are no studies showing improvement in hard outcomes or long-term prognosis. A possible reason is that vasopressin receptors have many downstream effects other than AQP2 function. It is expected that the development of drugs that directly target AQP2 may result in increased treatment specificity and effectiveness for water balance disorders. This review summarizes recent progress in studies of AQP2 and drug development challenges for water balance disorders.

Prediction of Molecular Interactions And Physicochemical Properties Relevant For Vasopressin V2 Receptor Antagonism

We have developed two ligand and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2 receptor (V2R) antagonist and eventually to predict the expected binding mode to V2R. The obtained Quantitative Structure Activity Relationship (QSAR) model showed a correlation of the antagonist activity with the hydration energy (EH2O) , the polarizability (P) and the calculated partial charge on atom N7 (q6) of the common substructure. The first two descriptors showed a positive contribution to antagonist activity, while the third one had a negative contribution. V2R was modeled and further relaxed on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC) membrane by molecular dynamics simulations. The receptor antagonist complexes were guessed by molecular docking, and the stability of the most relevant structures were also evaluated by molecular dynamics simulations. As a result, amino acid residues Q96, W99, F105, K116, F178, A194, F307, and M311 were identified with the probably most relevant antagonist-receptor interactions on the studied complexes. The proposed QSAR model could explain the molecular properties relevant to the antagonist activity. The contributions to the antagonist-receptor interaction appeared also in agreement with the binding mode of the complexes obtained by molecular docking and Molecular Dynamics. These models will be used in further studies to look for new V2R potential antagonist molecules.

Tolvaptan Response in a Hyponatremic Newborn with Syndrome of Inappropriate Secretion of Antidiuretic Hormone

The use of tolvaptan to treat both euvolemic and hypervolemic hyponatremia has rapidly increased in recent years. However, data on its effects on children, especially newborns and infants, are limited. Here, we present a newborn who developed syndrome of inappropriate secretion of antidiuretic hormone following an intracranial hematoma drainage operation who was unresponsive to conventional treatments. The infant was successfully treated with tolvaptan, a competitive inhibitor of the vasopressin V2 receptor.

Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation

Nephrogenic diabetes insipidus (NDI) is a rare tubulopathy characterized by urinary concentration defect due to renal resistance to vasopressin. Loss-of-function mutations of vasopressin V2 receptor (V2R) gene (AVPR2) is the most common cause of the disease. We have identified five novel mutations L86P, R113Q, C192S, M272R, and W323_I324insR from NDI-affected patients. Functional characterization of these mutants revealed that R113Q and C192S were normally localized at the basolateral membrane of polarized Madin-Darby Canine Kidney (MDCK) cells and presented proper glycosylation maturation. On the other side, L86P, M272R, and W323_I324insR mutants were retained in endoplasmic reticulum and exhibited immature glycosylation and considerably reduced stability. All five mutants were resistant to administration of vasopressin analogues as evaluated by defective response in cAMP release. In order to rescue the function of the mutated V2R, we tested VX-809, sildenafil citrate, ibuprofen and tolvaptan in MDCK cells. Among these, tolvaptan was effective in rescuing the function of M272R mutation, by both allowing proper glycosylation maturation, membrane sorting and response to dDAVP. These results show an important proof of concept for the use of tolvaptan in patients affected by M272R mutation of V2R causing NDI.