Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria

Abstract

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-3β (GSK-3β). Both COX1 and COX2 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 fourfold compared with 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, whereas COX1 levels remained unchanged. COX2 inhibition significantly blunted lithium-induced polyuria ( P < 0.0001) and reduced urinary 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 antidiuretic hormone (AHD)-deficient rats, demonstrating that lithium-induced COX2 protein expression is not secondary to altered ADH levels or polyuria. Lithium also decreased renal medullary GSK-3β 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 GSK-3 activity. In conclusion, these findings temporally link decreased GSK-3 activity to enhanced renal COX2 expression and COX2-derived urine PGE2 excretion. Suppression of COX2-derived PGE2 blunts lithium-associated polyuria.