Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1995 April; 95(4): 1838–1845.
PMCID: PMC295720

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


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 immunofluorescence and immunoelectronmicroscopy. 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/microns 2). 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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Peet M, Pratt JP. Lithium. Current status in psychiatric disorders. Drugs. 1993 Jul;46(1):7–17. [PubMed]
  • Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis. 1987 Nov;10(5):329–345. [PubMed]
  • Walker RG. Lithium nephrotoxicity. Kidney Int Suppl. 1993 Jul;42:S93–S98. [PubMed]
  • Christensen S, Kusano E, Yusufi AN, Murayama N, Dousa TP. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest. 1985 Jun;75(6):1869–1879. [PMC free article] [PubMed]
  • Sugawara M, Hashimoto K, Ota Z. Involvement of prostaglandin E2, cAMP, and vasopressin in lithium-induced polyuria. Am J Physiol. 1988 Jun;254(6 Pt 2):R863–R869. [PubMed]
  • Yamaki M, Kusano E, Tetsuka T, Takeda S, Homma S, Murayama N, Asano Y. Cellular mechanism of lithium-induced nephrogenic diabetes insipidus in rats. Am J Physiol. 1991 Sep;261(3 Pt 2):F505–F511. [PubMed]
  • Agre P, Preston GM, Smith BL, Jung JS, Raina S, Moon C, Guggino WB, Nielsen S. Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol. 1993 Oct;265(4 Pt 2):F463–F476. [PubMed]
  • Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S. Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature. 1993 Feb 11;361(6412):549–552. [PubMed]
  • Nielsen S, DiGiovanni SR, Christensen EI, Knepper MA, Harris HW. Cellular and subcellular immunolocalization of vasopressin-regulated water channel in rat kidney. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11663–11667. [PubMed]
  • DiGiovanni SR, Nielsen S, Christensen EI, Knepper MA. Regulation of collecting duct water channel expression by vasopressin in Brattleboro rat. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8984–8988. [PubMed]
  • Deen PM, Verdijk MA, Knoers NV, Wieringa B, Monnens LA, van Os CH, van Oost BA. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science. 1994 Apr 1;264(5155):92–95. [PubMed]
  • Christensen S, Agner T. Effects of lithium on circadian cycles in food and water intake, urinary concentration and body weight in rats. Physiol Behav. 1982 Apr;28(4):635–640. [PubMed]
  • Nielsen S, Smith BL, Christensen EI, Knepper MA, Agre P. CHIP28 water channels are localized in constitutively water-permeable segments of the nephron. J Cell Biol. 1993 Jan;120(2):371–383. [PMC free article] [PubMed]
  • Harris HW, Jr, Zeidel ML, Jo I, Hammond TG. Characterization of purified endosomes containing the antidiuretic hormone-sensitive water channel from rat renal papilla. J Biol Chem. 1994 Apr 22;269(16):11993–12000. [PubMed]
  • Sasaki S, Fushimi K, Saito H, Saito F, Uchida S, Ishibashi K, Kuwahara M, Ikeuchi T, Inui K, Nakajima K, et al. Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct. J Clin Invest. 1994 Mar;93(3):1250–1256. [PMC free article] [PubMed]
  • Lankford SP, Chou CL, Terada Y, Wall SM, Wade JB, Knepper MA. Regulation of collecting duct water permeability independent of cAMP-mediated AVP response. Am J Physiol. 1991 Sep;261(3 Pt 2):F554–F566. [PubMed]
  • Christensen S. DDAVP (1-desamino-8-D-arginine-vasopressin) treatment of lithium-induced polyuria in the rat. Scand J Clin Lab Invest. 1980 Apr;40(2):151–157. [PubMed]
  • Christensen S. Acute and chronic effects of vasopressin in rats with lithium-polyuria. Acta Pharmacol Toxicol (Copenh) 1976 Mar;38(3):241–253. [PubMed]
  • Christensen S, Hansen BB, Faarup P. Functional and structural changes in the rat kidney by long-term lithium treatment. Ren Physiol. 1982;5(2):95–104. [PubMed]
  • EPSTEIN FH, KLEEMAN CR, HENDRIKX A. The influence of bodily hydration on the renal concentrating process. J Clin Invest. 1957 May;36(5):629–634. [PMC free article] [PubMed]
  • Seif SM, Zenser TV, Ciarochi FF, Davis BB, Robinson AG. DDAVP (1-desamino-8-D-arginine-vasopressin) treatment of central diabetes insipidus--mechanism of prolonged antidiuresis. J Clin Endocrinol Metab. 1978 Mar;46(3):381–388. [PubMed]
  • Kirchner KA. Effect of diuretic and antidiuretic agents on lithium clearance as a marker for proximal delivery. Kidney Int Suppl. 1990 Mar;28:S22–S25. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation