Nielsen, J. et al. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc. Natl Acad. Sci. USA 105, 3634-3639

Water and Salt Research Center, University of Aarhus, DK-8000 Aarhus C, Denmark.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2008; 105(9):3634-9. DOI: 10.1073/pnas.0800001105
Source: PubMed


Lithium is a commonly prescribed mood-stabilizing drug. However, chronic treatment with lithium induces numerous kidney-related side effects, such as dramatically reduced aquaporin 2 (AQP2) abundance, altered renal function, and structural changes. As a model system, inner medullary collecting ducts (IMCD) isolated from rats treated with lithium for either 1 or 2 weeks were subjected to differential 2D gel electrophoresis combined with mass spectrometry and bioinformatics analysis to identify (i) signaling pathways affected by lithium and (ii) unique candidate proteins for AQP2 regulation. After 1 or 2 weeks of lithium treatment, we identified 6 and 74 proteins with altered abundance compared with controls, respectively. We randomly selected 17 proteins with altered abundance caused by lithium treatment for validation by immunoblotting. Bioinformatics analysis of the data indicated that proteins involved in cell death, apoptosis, cell proliferation, and morphology are highly affected by lithium. We demonstrate that members of several signaling pathways are activated by lithium treatment, including the PKB/Akt-kinase and the mitogen-activated protein kinases (MAPK), such as extracellular regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38. Lithium treatment increased the intracellular accumulation of beta-catenin in association with increased levels of phosphorylated glycogen synthase kinase type 3beta (GSK3beta). This study provides a comprehensive analysis of the proteins affected by lithium treatment in the IMCD and, as such, provides clues to potential lithium targets in the brain.

Download full-text


Available from: Robert A Fenton,
  • Source
    • "Patients with bipolar disorder generally respond well to lithium treatment, but the side effects on urinary concentrating ability often cause polyuria and polydipsia. Lithium appears to enter the principal cells of the collecting duct through the epithelial sodium channel ENaC and reduces aquaporin-2 expression [29]. Long-term treatment with lithium may induce tubulo-interstitial nephritis that can lead to irreversible NDI and end-stage renal failure [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The treatment of hyponatraemia due to SIADH is not always as straightforward as it seems. Although acute treatment with hypertonic saline and chronic treatment with fluid restriction are well established, both approaches have severe limitations. These limitations are not readily overcome by addition of furosemide, demeclocycline, lithium or urea to the therapy. In theory, vasopressin-receptor antagonists would provide a more effective method to treat hyponatraemia, by virtue of their ability to selectively increase solute-free water excretion by the kidneys (aquaresis). In this review we explore the limitations of the current treatment of SIADH and describe emerging therapies for the treatment of SIADH-induced hyponatraemia.
    NDT Plus 11/2009; 2(Suppl_3):iii12-iii19. DOI:10.1093/ndtplus/sfp154
    • "Urine volume increased three-fold after one week of lithium treatment and > six-fold after two weeks while AQP2 expression decreased to 58% of that in control rats at one week and to 33% at two weeks of lithium treatment. With the aid of proteomics, 77 different proteins were identified within the inner medullary collecting duct that were affected directly or indirectly by lithium treatment.20 Another cause of acquired NDI is postobstructive diuresis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Water is the most abundant molecule in any cell. Specialized membrane channel, proteins called aquaporins, facilitate water transport across cell membranes. At least seven aquaporins (AQP): 1, 2, 3, 4, 6, 7, and 11 are expressed in the kidneys. Aquaporins play a role in both the short-term and long-term regulation of water balance as well as in the pathophysiology of water balance disorders. Aquaporin is composed of a single peptide chain consisting of approximately 270 amino acids. Inherited central and nephrogenic diabetes insipidus are primarily due to the decreased expression of AQP2 while mutation in the AQP2 molecule is responsible for inherited central diabetes insipidus. In acquired causes of nephrogenic diabetes insipidus, there is a downregulation of AQP2 expression in the inner medulla of the kidney. Nephrotic syndrome is characterized by excessive sodium and water reabsorption, although in spite of this, patients do not develop hyponatremia. There is a marked downregulation of both AQP2 and AQP3 expression, which could be a physiologic response to extracellular water reabsorption in patients with nephrotic syndrome. There are some conditions in which aquaporin expression has been found to increase such as experimentally induced heart failure, cirrhosis, and pregnancy. Some drugs such as cisplatin and cyclosporine, also alter the expression of aquaporins. The three-pore model of peritoneal transport depicts the importance of aquaporins. Thus, the understanding of renal water channels has solved the mystery behind many water balance disorders. Further insights into the molecular structure and biology of aquaporins will help to lay a foundation for the development of future drugs.
    Indian Journal of Nephrology 07/2008; 18(3):95-100. DOI:10.4103/0971-4065.43687
  • Source

Show more