Changes of rat kidney AQP2 and Na,K-ATPase mRNA expression in lithium-induced nephrogenic diabetes insipidus.
OBJECTIVE
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.


METHODS
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 insipidus and moderately decreased Na,K-ATPase mRNA levels in the ISOM and in the IM.


CONCLUSIONS
The results suggest that decreased mRNA expressions of AQP2 and Na,K-ATPase contribute to the development of lithium-induced nephrogenic diabetes insipidus.
Laursen
Ulla Helt
UH
Water and Salt Research Center and Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark.
Pihakaski-Maunsbach
Kaarina
K
Kwon
Tae-Hwan
TH
Østergaard Jensen
Erik
E
Nielsen
Søren
S
Maunsbach
Arvid B
AB
D000818:Animals; D051399:Aquaporin 2; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism*; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000648:ultrastructure; D008094:Lithium / Q000633:toxicity*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*
C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D012333:RNA, Messenger; D008094:Lithium; D000254:Sodium-Potassium-Exchanging ATPase