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-3␤ (GSK-3␤). 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 Ͻ 0.0001) and was accompanied by decreased urine osmolality. This was temporally associated with increased renal COX2 protein expression and increased urinary PGE 2 excretion, whereas COX1 levels remained unchanged. COX2 inhibition significantly blunted lithium-induced polyuria (P Ͻ 0.0001) and reduced urinary PGE2 levels. Lithium-associated polyuria was also seen in COX1Ϫ/Ϫ mice and was associated with increased urinary PGE2. COX2 inhibition completely prevented polyuria and PGE2 excretion in COX1Ϫ/Ϫ 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 lithiuminduced COX2 protein expression is not secondary to altered ADH levels or polyuria. Lithium also decreased renal medullary GSK-3␤ 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. prostaglandin E2; urine osmolality LITHIUM, A METALLIC MONOVALENT cation, has been used therapeutically for more than 150 years and remains an important pharmacotherapeutic agent for treatment of bipolar disorder and Alzheimer's disease (10,24,34). It is estimated that ϳ1 of every 1,000 individuals in the population is on lithium treatment (33). The use of lithium is frequently complicated by impaired renal water reabsorption, resulting in nephrogenic diabetes insipidus (NDI) (3). The mechanism by which lithium induces diabetes insipidus is incompletely understood. Sugawara et al. (31) reported that after LiCl treatment, rats exhibit increased urinary PGE 2 excretion. They also found the nonselective cyclooxygenase-inhibiting NSAID indomethacin reduced lithium-induced PGE 2 excretion and polyuria, suggesting that a diuretic cyclooxygenase product may be involved in lithium-associated diabetes insipidus. COX2, an inducible isoform of cyclooxygenase, is expressed in the kidney together with COX1, a constitutively exp...

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

“…GSK3, which is inhibited noncompetitively by lithium (16,17), has been studied extensively for its role in cell proliferation and epithelial-mesenchymal transition (13). In our study, lithium treatment resulted in a marked increase in phosphorylated (inactive) GSK3␤, in line with previous studies (18). Because GSK3␤ is a target for phosphorylation by Akt, the increased p-Akt observed with lithium treatment is the potential upstream regulator of this signaling cascade (see above).…”

“…However, it has been shown that inhibition of GSK3␤ by lithium results in enhanced renal COX2 expression in interstitial cells, leading to an increase in local PGE(2) excretion (18), that in turn may counteract AVP actions by causing endocytic retrieval of AQP2 from the collecting duct plasma membrane, thus impairing urinary concentrating ability (20). GSK3␤ knockout mice die from liver degeneration (21); thus, the consequence of GSK3␤ gene deletion on kidney function has yet to be examined.…”

Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice

“…A feedback mechanism limits insulininduced sodium retention when extracellular fluid volume is expanded [40], which is impaired in rats with hypertension associated with insulin resistance [41]. Inhibition of GSK3 by lithium has been shown to cause urinary concentrating defects [42] and also could inhibit sodium reabsorption in the collecting duct. Renal sodium handling is critical for the maintenance of extracellular fluid volume and BP and its impairment has been associated with the development of hypertension [43,44].…”

Lithium in the Kidney: Friend and Foe?

“…51,52 How the inhibition of GSK3 by lithium ultimately leads to NDI has not been identified but may involve b-catenin, which is increased in expression in lithiuminduced NDI and targeted for degradation by GSK3. 48,[53][54][55] Although basal b-catenin activity is necessary for AQP2 expression in collecting duct cell cultures, overactivation of the canonical Wnt-b-catenin pathway might contribute to lithiuminduced NDI, because it induces transcription of proliferative genes, which is also observed in principal cells of lithium-treated rodents. 56,57 Loss of polarization, which occurs with proliferation, reduces AQP2 expression in vitro.…”