Lithium therapy frequently induces nephrogenic diabetes insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site for lithium and the beneficial effect of amiloride may be through inhibiting lithium entry. Using a mouse collecting duct cell line, we found that vasopressin caused an increase in Aquaporin 2 (AQP2) expression which was reduced by clinically relevant lithium concentrations similar to what is seen with in vivo models of this disease. Further amiloride or benzamil administration prevented this lithium-induced downregulation of AQP2. Amiloride reduced transcellular lithium transport, intracellular lithium concentration, and lithium-induced inactivation of glycogen synthase kinase 3beta. Treatment of rats with lithium downregulated AQP2 expression, reduced the principal-to-intercalated cell ratio, and caused polyuria, while simultaneous administration of amiloride attenuated all these changes. These results show that ENaC is the major entry site for lithium in principal cells both in vitro and in vivo. Blocking lithium entry with amiloride attenuates lithium-induced diabetes insipidus, thus providing a rationale for its use in treating this disorder.

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Background:The sodium chloride cotransporter NCC mediates NaCl reabsorption in the kidney distal convoluted tubule. Results: NCC internalization from the plasma membrane is clathrin-mediated and regulated by NCC phosphorylation and ubiquitylation. Conclusion: Phosphorylation of NCC can regulate NCC internalization and ubiquitylation. Significance: Impaired NCC endocytosis could be implicated in salt-sensitive hypertension in vivo.

Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocation of aquaporin-2 to the apical membrane. Moreover, in contrast to plasma membrane V2R, degradation of intracellular V2R mutants is not increased by their activation. Our data reveal that G protein-coupled receptors (GPCRs) normally active at the plasma membrane can be activated intracellularly and that intracellular activation does not induce their degradation; the data also indicate that nonpeptide agonists constitute highly promising therapeutics for diseases caused by misfolded GPCRs in general, and NDI in particular.GPCR ͉ pharmacological chaperones ͉ signaling ͉ ER retention ͉ osmoregulation

Arginine vasopressin (AVP) is released from the posterior pituitary gland during states of hyperosmolality or hypovolemia. AVP is a peptide hormone, with antidiuretic and antinatriuretic properties. It allows the kidneys to increase body water retention predominantly by increasing the cell surface expression of aquaporin water channels in the collecting duct alongside increasing the osmotic driving forces for water reabsorption. The antinatriuretic effects of AVP are mediated by the regulation of sodium transport throughout the distal nephron, from the thick ascending limb through to the collecting duct, which in turn partially facilitates osmotic movement of water. In this review, we will discuss the regulatory role of AVP in sodium transport and summarize the effects of AVP on various molecular targets, including the sodium-potassium-chloride cotransporter NKCC2, the thiazide-sensitive sodium-chloride cotransporter NCC, and the epithelial sodium channel ENaC.