Lithium reduces aquaporin-2 transcription independent of prostaglandins

Kortenoeven, Marleen L. A.; Schweer, Horst; Cox, Rik; Wetzels, Jack F.M.; Deen, Peter M.T.

doi:10.1152/ajpcell.00197.2011

Cited by 44 publications

(41 citation statements)

References 63 publications

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“…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.…”

Section: Toxic Effects Of Lithium Treatmentmentioning

confidence: 99%

Lithium in the Kidney: Friend and Foe?

Alsady

Baumgarten²,

Deen

et al. 2015

JASN

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Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for .60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD.

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Section: Toxic Effects Of Lithium Treatmentmentioning

confidence: 99%

Lithium in the Kidney: Friend and Foe?

Alsady

Baumgarten²,

Deen

et al. 2015

JASN

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“…Previous studies have shown that pharmacological inhibition of GSK3 using LiCl, Zn, and 6-bromoindirubin-3=-oxime can reduce AQP2 levels in in vitro cell culture systems (20,21,24). However, these inhibitors are incapable of distinguishing between GSK3␣ and GSK3␤ isoforms.…”

Section: Gsk3␣ Is Expressed In Renal Collecting Ductsmentioning

confidence: 99%

“…NDI is the most frequently found undesirable effect of Li ϩ therapy, and it is found in up to 40% of patients (10,42). The primary cause of Li ϩ -induced NDI is the decrease in renal AQP2 expression (10), for which several mechanisms have been proposed, including altered AVP/cAMP and cyclooxygenase-2/PGE 2 signaling (4,21,23,24,37).…”

Section: Gsk3␣ Is An Important Regulator Of Renal Urine Concentrationmentioning

confidence: 99%

Glycogen synthase kinase 3α regulates urine concentrating mechanism in mice

Nørregaard

Tao

Nilsson

et al. 2015

American Journal of Physiology-Renal Physiology

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In mammals, glycogen synthase kinase (GSK)3 comprises GSK3␣ and GSK3␤ isoforms. GSK3␤ has been shown to play a role in the ability of kidneys to concentrate urine by regulating vasopressin-mediated water permeability of collecting ducts, whereas the role of GSK3␣ has yet to be discerned. To investigate the role of GSK3␣ in urine concentration, we compared GSK3␣ knockout (GSK3␣KO) mice with wild-type (WT) littermates. Under normal conditions, GSK3␣KO mice had higher water intake and urine output. GSK3␣KO mice also showed reduced urine osmolality and aquaporin-2 levels but higher urinary vasopressin. When water deprived, they failed to concentrate their urine to the same level as WT littermates. The addition of 1-desamino-8-D-arginine vasopressin to isolated inner medullary collecting ducts increased the cAMP response in WT mice, but this response was reduced in GSK3␣KO mice, suggesting reduced responsiveness to vasopressin. Gene silencing of GSK3␣ in mpkCCD cells also reduced forskolin-induced aquaporin-2 expression. When treated with LiCl, an isoform nonselective inhibitor of GSK3 and known inducer of polyuria, WT mice developed significant polyuria within 6 days. However, in GSK3␣KO mice, the polyuric response was markedly reduced. This study demonstrates, for the first time, that GSK3␣ could play a crucial role in renal urine concentration and suggest that GSK3␣ might be one of the initial targets of Li ϩ in LiCl-induced nephrogenic diabetes insipidus.glycogen synthase kinase 3␣; glycogen synthase kinase 3␤; urine concentration; vasopressin; lithium REGULATION OF WATER HOMEOSTASIS is a critical function of the kidneys. When arginine vasopressin (AVP) binds to its V2 receptors on principal cells of renal collecting ducts, it leads to activation of adenylate cyclase, which triggers an elevation of cAMP. cAMP-mediated activation of PKA leads to increased trafficking of aquaporin (AQP)2 to the apical membrane, resulting in water reabsorption from the tubular fluid and the production of concentrated urine (1,27,47). Recent studies have demonstrated that the glycogen synthase kinase (GSK)3 family of serine/threonine protein kinases plays an important role in renal urine concentration (34). This concept originated from the observation that Li ϩ , a common treatment for bipolar disorders that causes an AVP-insensitive form of urinary concentrating defect, is also an effective inhibitor of GSK3 (10,30,32,37,40,42,49).The mammalian GSK3 isoforms, GSK3␣ and GSK3␤, were thought to be redundant in their function because they share 98% sequence identity in their catalytic domains (17). Moreover, deletion of all four alleles of GSK3␣ and GSK3␤ was required to significantly increase ␤-catenin, a substrate negatively regulated by GSK3, suggesting that the isoforms could compensate for each other (7). However, recent studies have also shown that GSK3 isoforms could have unique functions. For example, in Drosophila carrying a mutation in ZW3/ Shaggy, the fly ortholog of mammalian GSK3, GSK3␤ rescued the frizzled phenotype more e...

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“…[9][10][11] Lithium also affects AQP2-mediated water reabsorption by the elevated tubular release of prostaglandin E 2 . [11][12][13] In a second phase, lithium reduces the percentage of principal cells in the collecting duct, which are "exchanged" for intercalated cells, involved in acid-base homeostasis. 14 Paradoxically, but in line with increased Wnt/b-catenin induced activity, 15,16 lithium is known to induce proliferation of principal cells.…”

mentioning

confidence: 99%

Lithium Causes G2 Arrest of Renal Principal Cells

Groot

Alsady

Jaklofsky

et al. 2014

Journal of the American Society of Nephrology

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Vasopressin-regulated expression and insertion of aquaporin-2 channels in the luminal membrane of renal principal cells is essential for urine concentration. Lithium affects urine concentrating ability, and approximately 20% of patients treated with lithium develop nephrogenic diabetes insipidus (NDI), a disorder characterized by polyuria and polydipsia. Lithium-induced NDI is caused by aquaporin-2 downregulation and a reduced ratio of principal/intercalated cells, yet lithium induces principal cell proliferation. Here, we studied how lithium-induced principal cell proliferation can lead to a reduced ratio of principal/intercalated cells using two-dimensional and three-dimensional polarized cultures of mouse renal collecting duct cells and mice treated with clinically relevant lithium concentrations. DNA image cytometry and immunoblotting revealed that lithium initiated proliferation of mouse renal collecting duct cells but also increased the G2/S ratio, indicating G2/M phase arrest. In mice, treatment with lithium for 4, 7, 10, or 13 days led to features of NDI and an increase in the number of principal cells expressing PCNA in the papilla. Remarkably, 30%-40% of the PCNA-positive principal cells also expressed pHistone-H3, a late G2/M phase marker detected in approximately 20% of cells during undisturbed proliferation. Our data reveal that lithium treatment initiates proliferation of renal principal cells but that a significant percentage of these cells are arrested in the late G2 phase, which explains the reduced principal/intercalated cell ratio and may identify the molecular pathway underlying the development of lithium-induced renal fibrosis.

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Lithium reduces aquaporin-2 transcription independent of prostaglandins

Cited by 44 publications

References 63 publications

Lithium in the Kidney: Friend and Foe?

Lithium in the Kidney: Friend and Foe?

Glycogen synthase kinase 3α regulates urine concentrating mechanism in mice

Lithium Causes G2 Arrest of Renal Principal Cells

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