Changes of Rat Kidney AQP2 and Na,K-ATPase mRNA Expression in Lithium-Induced Nephrogenic Diabetes Insipidus

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Title: Changes of Rat Kidney AQP2 and Na,K-ATPase mRNA Expression in Lithium-Induced Nephrogenic Diabetes Insipidus
Authors: Laursen, Ulla H.; Pihakaski-Maunsbach, PhD, Kaarina; Kwon, Tae-Hwan; Jensen, Erik Ostergaard; Nielsen, Soren; Maunsbach, MD, dr.med.sci., Arvid B.
Publisher: Nephron
Date Published: January 01, 2004
Reference Number: 650
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BACKGROUND/AIM: In a rat model, lithium treatment is associated with polyuria and severe downregulation of aquaporin-2 (AQP2) protein in the inner medulla (IM) or in the whole kidney. However, it is not known (1) to what extent this downregulation occurs at the mRNA level; (2) whether the main sodium transporter of the nephron, Na,K-ATPase, is regulated in parallel at the mRNA level, and (3) whether lithium treatment induces zonal or segmental differences in AQP2 and Na,K-ATPase mRNA levels. METHOD: We examined the changes in mRNA expression levels for AQP2 and Na,K-ATPase in kidney cortex, inner stripe of the outer medulla (ISOM), and IM of rats treated with lithium orally using semiquantitative Northern blot analyses and in situ hybridization at the light and electron microscopic levels. RESULTS: The AQP2 mRNA levels decreased significantly (p < 0.01) in lithium-treated rats to 37 +/- 4% in the cortex, to 17 +/- 4% in the ISOM, and to 23 +/- 5% in the IM, while the Na,K-ATPase mRNA levels were not altered in the cortex, but were significantly (p < 0.05) altered in the ISOM (144 +/- 15% after 10 days, but 68 +/- 4% after 4 weeks) and in the IM (63 +/- 8% after 10 days, but normalized after 4 weeks). In situ hybridization showed reduced levels of AQP2 mRNA in all zones of the kidney, but the Na,K-ATPase mRNA expressions were slightly decreased only in IM collecting ducts. At the ultrastructural level, principal cells in the IM collecting ducts showed slight hypertrophy, but no cell damage after 4 weeks of lithium treatment. The results demonstrate substantial downregulation of AQP2 at the mRNA level throughout the collecting duct in experimental lithium-induced nephrogenic dabetes [sic] insipidus and moderately decreased Na,K-ATPase mRNA levels in the ISOM and in the IM. CONCLUSION: The results suggest that decreased mRNA expressions of AQP2 and Na,K-ATPase contribute to the development of lithium-induced nephrogenic diabetes insipidus. Copyright 2004 S. Karger AG, Basel

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

NDI is a common side effect of chronic ingestion of lithium. This is because chronic lithium consumption reduces the amount of aquaporin 2 (AQP2) in the principal cells of the kidney collecting duct. How it does this is unclear. Nevertheless, AQP2 plays a vital role in the kidney’s ability to concentrate urine by acting as a channel through which water may enter the cell.

Another process that must occur for the kidney to be able to reabsorb water, and thus concentrate urine, is the transport of sodium (Na+) throughout the kidney. Na,K-ATPase is the major Na+ transporter in the kidney. Pathological conditions in the kidney, such as NDI, can reduce the numbers of Na,K-ATPase.

Laursen, et al., conducted experiments with groups of rats, using some as a control group and feeding different experimental groups the same amount of lithium, but for different lengths of time (group 1 – 10 days; group 2 – 14 days; group 3 – 28 days). The research team sought to determine if the reduction of AQP2 levels correlate with the reduction of AQP2 mRNA. Messenger ribonucleic acid moleculesmRNA – are those molecules that serve as templates for protein synthesis. AQP2 mRNA is that mRNA that serves as a template for AQP2 synthesis. Without it, the AQP2 could not synthesize, i.e. become a protein. The team also wanted to determine whether lithium treatment is associated with Na,K-ATPase mRNA levels in the kidney, and to see if different regions of the kidney – the inner stripe of the outer medulla (ISOM), the inner medulla (IM) and the cortexexpressed differences in the regulation of AQP2 and Na,K-ATPase mRNA levels in response to lithium.

Using multiple means of measurement, Laursen, et al., discovered that AQP2 mRNA levels significantly decreased in the experimental rats in all regions of the kidney measured. Lithium did not alter Na,K-ATPase mRNA levels in the kidney cortex, but did alter the levels in the ISOM and IM. (These reductions were smaller than those of AQP2 mRNA, but clearly occurred.) Na,K-ATPase mRNA levels returned to normal in the cortex after 4 weeks.

The actual physical structure of the principal cells in the IM changed, becoming larger. This increase in size was not accompanied by any cell damage. In the end, the data revealed that lithium treatment causes a severe reduction in the number of AQP2 mRNA in all regions of the experimental rats’ kidneys. This correlates with the reduction of AQP2s in the kidney. The reduction of Na,K-ATPase mRNA indicates that Na,K-ATPase plays a role in the development of lithium-induced NDI and may, in part, explain why recovery after lithium treatment is a slow process.