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1 Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
2 Department of Health Science Research, Vanderbilt University Medical Center, Nashville, TN, USA
3 Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; VA Medical Center, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: chuanming.hao{at}vanderbilt.edu.
The use of LiCl in clinical psychiatry is routinely complicated by overt nephrogenic diabetes insipidus (nDI), the mechanism of which is incompletely understood. In vitro studies indicate that lithium can induce renal medullary interstitial cell cyclooxygenase 2 (COX2) protein expression via inhibition of glycogen synthase kinase 3
(GSK3). Both COX 1 and COX 2 are expressed in the kidney. Renal prostaglandins have been suggested to play an important role in lithium induced
polyuria. The present studies examined whether induction of the COX2 isoform contributes to LiCl induced polyuria. Four days after initiation of lithium treatment in C57 BL/6J mice, urine volume increased in LiCl treated mice by 4 fold compared to controls (p<0.0001), and was accompanied by decreased urine osmolality. This was temporally associated with increased renal COX2 protein
expression and increased urinary PGE2 excretion, while COX1 levels remained unchanged. COX2
inhibition significantly blunted Li induced polyuria (P<0.0001), and reduced urinary prostaglandin E2
(PGE2) levels. Lithium associated polyuria was also seen in COX1-/- mice and was associated with
increased urinary PGE2. COX2 inhibition completely prevented polyuria and PGE2 excretion in COX1-/- mice, suggesting that COX2, but not COX1 plays a critical role in lithium induced polyuria.
Lithium also induced renal medullary COX2 protein expression in congenitally polyuric ADH deficient rats, demonstrating that lithium induced COX2 protein expression is not secondary to altered ADH levels or polyuria. Lithium also decreased renal medullary GSK3 activity and this was temporally related to increased COX2 expression in the kidney from lithium treated mice, consistent with a tonic in vivo suppression of COX2 expression by GSK3 activity. In conclusion, these findings
temporally link decreased GSK3 activity to enhanced renal COX2 expression and COX2 derived urine PGE2 excretion. Suppression of COX2 derived PGE2 blunts lithium associated polyuria.
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