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1 University of Aarhus, The Water and Salt Research Center, DK-8000 Aarhus, Denmark; University of Aarhus, Institute of Anatomy, DK-8000 Aarhus, Denmark
2 University of Leeds, School of Biomedical Sciences, Leeds LS2 9NQ, United Kingdom
3 University of Aarhus, The Water and Salt Research Center, DK-8000 Aarhus, Denmark; University of Aarhus, Institute of Experimental Research, DK-8000 Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
Lithium treatment for 4 weeks caused severe polyuria, dramatic downregulation in AQP2 expression and a marked decrease in AQP2 immunoreactivity with the appearance of a large number of cells without AQP2 labeling in the collecting ducts after lithium treatment. Surprisingly this was not all due to an increase in AQP2 negative cells, since double immunolabeling revealed that the major part of the AQP2 negative cells displayed H+-ATPase labeling identifying 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 exhibits detectable AQP2 labeling compared to control rats: 40 ± 3.4% vs. 62 ± 1.8% in controls (p<0.05, n=4) in cortical collecting duct and 58 ± 1.6% vs. 81 ± 1.3% in controls (p<0.05, n=4) in inner medullary collecting duct. In parallel a significant increase in the fraction of intercalated cells (H+-ATPase positive) was shown. Urine output, whole kidney AQP2 expression, cellular organization, and the fraction of principal and intercalated cells in cortex and inner medulla returned to control levels after 4 weeks on lithium-free diet following 4 weeks on a lithium-containing diet. In conclusion, lithium treatment not only decreases AQP2 expression, but dramatically and reversibly reduces the fraction of principal cells and alters the cellular organization in the collecting duct. These effects are likely to be important in lithium-induced NDI.
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