Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI

• Published in: American Journal of Physiology: Cell Physiology 2004-04, Vol.286 (4), p.C952-C964
• Main Authors: Christensen, Birgitte Monster, Marples, David, Kim, Young-Hee, Wang, Weidong, Frokiaer, Jorgen, Nielsen, Soren
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Aquaporin 2; Aquaporin 4; Aquaporin 6; Aquaporins - immunology; Aquaporins - metabolism; Carrier Proteins - immunology; Carrier Proteins - metabolism; Diabetes Insipidus, Nephrogenic - chemically induced; Diabetes Insipidus, Nephrogenic - metabolism; Down-Regulation - drug effects; Kidney Tubules, Collecting - drug effects; Kidney Tubules, Collecting - metabolism; Kidney Tubules, Collecting - ultrastructure; Lithium - pharmacology; Membrane Transport Proteins; Microscopy, Immunoelectron; Proton-Translocating ATPases - immunology; Proton-Translocating ATPases - metabolism; Rats; Rats, Wistar; Recovery of Function; Urine
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00266.2003

1 Water and Salt Research Center, 2 Institute of Anatomy, and 4 Institute of Experimental Clinical Research, University of Aarhus, DK-8000 Denmark; and 3 School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom Submitted 26 June 2003 ; accepted in final form 4 November 2003 Lithium treatment for 4 wk caused severe polyuria, dramatic downregulation in aquaporin-2 (AQP-2) expression, and marked decrease in AQP-2 immunoreactivity with the appearance of a large number of cells without AQP-2 labeling in the collecting ducts after lithium treatment. Surprisingly, this was not all due to an increase in AQP-2-negative principal cells, because double immunolabeling revealed that the majority of the AQP-2-negative cells displayed [H + ]ATPase labeling, which identified them as intercalated cells. Moreover, multiple [H + ]ATPase-labeled cells were adjacent, which was never seen in control rats. Quantitation confirmed a significant decrease in the fraction of collecting duct cells that exhibited detectable AQP-2 labeling compared with control rats: in cortical collecting ducts, 40 ± 3.4 vs. 62 ± 1.8% of controls ( P < 0.05; n = 4) and in inner medullary collecting ducts, 58 ± 1.6 vs. 81 ± 1.3% of controls ( P < 0.05; n = 4). In parallel, a significant increase in the fraction of intercalated ([H + ]ATPase-positive) cells was shown. Urine output, whole kidney AQP-2 expression, cellular organization, and the fractions of principal and intercalated cells in cortex and inner medulla returned to control levels after 4 wk on a lithium-free diet following 4 wk on a lithium-containing diet. In conclusion, lithium treatment not only decreased AQP-2 expression, but dramatically and reversibly reduced the fraction of principal cells and altered the cellular organization in collecting ducts. These effects are likely to be important in lithium-induced nephrogenic diabetes insipidus. nephrogenic diabetes insipidus; aquaporin; exchanger Address for reprint requests and other correspondence: S. Nielsen, Water and Salt Research Center, Institute of Anatomy, Univ. of Aarhus, DK-8000 Aarhus, Denmark (E-mail: sn{at}ana.au.dk ).