Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla.

Abstract

Lithium, a widely used treatment for bipolar affective disorders, often. causes nephrogenic diabetes insipidus. The effect of chronic lithium therapy on the expression of the vasopressin-regulated water channel Aquaporin-2 (AQP2) in rat kidney was examined. Membranes were prepared from inner medulla of one kidney from each rat, while the contralateral one was fixed for iminunofluorescence and immunoelectromnicroscopy. Immunoblotting revealed that lithium treatment reduced AQP2 expression dramatically, to 31±8% after 10 d and to 4±1% after 25 d, coincident with development of severe polyuria. Immunofluorescence and immunogold quantitation confirmed the lithium-induced decrease in AQP2 expression (from 11.2±1.0 to 1.1±0.2 particles/,um2). The downregulation was only partly reversed by return to lithium-free diet for 1 wk (40±8% of control). Furthermore, immunoblotting and immunogold quantitation revealed that 2 d of thirsting or 7 d of dDAVP treatment, in the continued presence of lithium, increased AQP2 expression by six-and threefold, respectively, coincident with increased urinary osmolality. Thirsting increased AQP2 immunolabeling mainly of vesicles, whereas dDAVP caused accumulation of AQP2 predominantly in the subapical region and plasma membrane. Thus, lithium causes marked downregulation of AQP2 expression, only partially reversed by cessation of therapy, thirsting or dDAVP treatment, consistent with clinical observations of slow recovery from lithium-induced urinary concentrating defects. (J. Clin. Invest. 1995. 95:1838-1845

Lithium in Kidney Diseases

“…16 Two major effects of lithium on collecting duct-downregulating AQP-2 expression and reducing the number of renal principal cells-have been suggested to contribute to NDI. 4 Consistent with previous reports, 17 de Groot et al showed that lithium induced downregulation of AQP-2 both in cultured murine principal collecting-duct cells and in kidneys. 11 Of note, lithium initiated the proliferation of murine principal collecting-duct cells and especially increased the number of the cells in S and G2 phase of the cell cycle.…”

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

“…In 50% of these patients, chronic lithium treatment is associated with altered renal function and nephrogenic diabetes insipidus (NDI) characterized by a defective urinary concentrating mechanism that manifests in polyuria, increased sodium excretion, and hypercholoremic metabolic acidosis (3). The polyuria is largely explained by decreased abundances of the vasopressin (AVP)-regulated aquaporin 2 and aquaporin 3 (AQP2 and AQP3) water channels in the collecting duct (4,5). The renal sodium loss is likely to be caused by reduced expression of the epithelial sodium channel (ENaC) in the cortical and outer medullary collecting duct (6,7).…”

Lithium-induced Nephrogenic Diabetes Insipidus

“…UT-A1 expression is in part regulated by AVP. This would suggest that amiloride and/or inhibition of lithium uptake may have indirect effects in addition to the specific changes well documented in the collecting tubules (26,27). This is also supported by the observation that, although urinary AQP2 excretion was increased, it did not parallel the increase in urinary osmolality.…”

“…Nielsen et al have demonstrated, in animal models, that lithium inhibits AVP-stimulated insertion of AQP2 into the apical membrane due to inhibition of adenyl cyclase, which is normally activated following binding of AVP to the V 2 receptor (11,12,26). On the other hand, Deen et al have demonstrated that cAMP and AQP2 downregulation may be at least partially independent of each other (28).…”