Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI.
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.
Christensen
Birgitte Mønster
BM
Water and Salt Research Center, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus, Denmark.
Marples
David
D
Kim
Young-Hee
YH
Wang
Weidong
W
Frøkiaer
Jørgen
J
Nielsen
Søren
S
D000818:Animals; D000906:Antibodies; D051399:Aquaporin 2; D051401:Aquaporin 4; D051403:Aquaporin 6; D020346:Aquaporins / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced* / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D008094:Lithium / Q000494:pharmacology*; D026901:Membrane Transport Proteins; D016253:Microscopy, Immunoelectron; D006180:Proton-Translocating ATPases / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D000076988:Sulfate Transporters; D014556:Urine
D000906:Antibodies; C496025:Aqp2 protein, rat; C496032:Aqp4 protein, rat; D051399:Aquaporin 2; D051401:Aquaporin 4; D051403:Aquaporin 6; D020346:Aquaporins; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D008094:Lithium; D006180:Proton-Translocating ATPases