A novel therapeutic effect of statins on nephrogenic diabetes insipidus

Abstract

Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional 'pleiotropic' effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed.

Keywords: HMG-CoA; apical membrane; aquaporin; cholesterol-lowering drugs; hypercholesterolaemia; kidney; nephrogenic diabetes insipidus; vasopressin; water channels.

Fig 1

Anatomic structure of the nephron and collecting duct system, and localization of different aquaporins (AQPs) in the kidneys with vasopressin (AVP) effect. Sites of reabsorption of water and sodium chloride (NaCl) are shown. AQP6 is localized in the intracellular vesicle membranes of type-A intercalated cells of the collecting duct.

Fig 2

The topology of AQP2 with the COOH-terminal phosphorylation sites. AQP2 is a tetramer consisting of four identical protein subunits placed in the plasma membrane. Six transmembrane α-helices are arranged in a right-handed bundle and are represented by cylinders, with the amino (NH2-) and the carboxyl (COOH-) termini located on the cytoplasmic surface of the membrane. Five interhelical loop regions (A–E) form the extracellular and cytoplasmic vestibules. Loops B and E are hydrophobic loops that contain the highly, although not completely conserved, asparagine–proline–alanine (NPA) motifs. Such motifs appear to dip and overlap into the membrane, to construct the water pore ,. Serine residues at potential phosphorylation sites are labelled with their amino acid numbers at the carboxyl-terminal tail. AVP mediated increased (+) phosphorylation at S256, S264 and S269, and decreased (−) phosphorylation at S261. Both S269 and S256 phosphorylation are involved in AQP2 accumulation in the plasma membrane ,,.

Fig 3

Molecular pathways involved in AQP2-mediated water transport in the kidney. (A) Signalling cascades and molecular pathways involved in AQP2-mediated water transport in relation to vasopressin (AVP) and vasopressin receptor (AVPR2) in the principal cells of the collecting ducts ,,,. The increased influx of water by AQP2 tetramer at the apical site requires a complex cascade of intracellular processes in concert with efflux of water by AQP3 and AQP4 tetramers at the basolateral membrane. The AVPR2 is composed of 7 membrane-spanning helices. Upon binding of AVP within the transmembrane helices II–IV, allosteric structural changes occur ,, the G-alpha-s heterodimeric protein is stimulated, and activates the adenylyl cyclase. This step results in increased intracellular levels of cyclic adenosine monophosphate (cAMP), activation of protein kinase A (PKA), phosphorylation of AQP2 in intracellular vesicles at serine 256 and other residues in the AQP2 OOH terminal , (see also Fig.2), trafficking of endocytic vesicles to the apical plasma membrane, and fusion of AQP2-containing vesicles with the apical membrane. As stated in the text, PKA is also responsible for phosphorylation of the membrane-associated RhoA, association with GDI to form the inactive complex RhoA-GDI, a step facilitating AQP2 insertion into the plasma membrane during VP/PKA/cAMP-induced AQP2 translocation . The docking system for vesicles might include specific receptors in the collecting duct cells which are associated with certain membrane domains housing AQP2 (e.g. syntaxin-4). Abbreviation: PDEs, phosphodiesterases. See also ,,,. (B) Proposed model of transcytotic trafficking of AQP2 from basolateral to apical membrane in principal cell of the collecting ducts. At least eight steps are involved: (1) Synthesis in the endoplasmic reticulum and transport to the trans-Golgi network; (2) rapid insertion of AQP2 into the basolateral membrane; (3) rapid internalization by clathrin-dependent endocytosis which is responsible for limited expression of basolateral AQP2. This step is blockable by low temperature (4°C); (5) AQP2 transcytosis to the perinuclear recycling compartment and the apical recycling endosomes via the microtubule-dependent mechanism. This step is inhibitable by colchicine; (7) exocytosis of AQP2 at the apical membrane; (8) recycling of AQP2 towards the apical recycling endosomes via the clathrin-dependent endocytosis. Thin dotted arrows show alternative pathways (?) of AQP2. Asterisks indicate where vasopressin (AVP) stimulus is inducing increased exocytosis and recycling of AQP2 with effect on transepithelial water flux (apical side) and cell migration, tubulogenesis, and likely transepithelial water flux (basolateral side). See also ,.