Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

Abstract

In antidiuresis, vasopressin (AVP) occupation of V2 receptors in renal collecting ducts activates adenylyl cyclase, resulting in increased intracellular cAMP levels, which activates protein kinase A (PKA). PKA phosphorylates both the cAMP responsive element binding protein, which induces aquaporin-2 (AQP2) transcription, and AQP2, which then is translocated to the apical membrane, allowing urine concentration. Lithium treatment often causes nephrogenic diabetes insipidus (NDI), which coincides with decreased AQP2 expression and which generally is ascribed to reduced adenylyl cyclase activity. However, the underlying mechanism by which lithium causes NDI is poorly understood. This study demonstrated that the mouse cortical collecting duct mpkCCD c14 cells are a good model; the deamino-8 D-arginine vasopressin (dDAVP)-induced endogenous AQP2 expression and plasma membrane localization was time-dependently reduced by treatment with clinically relevant lithium concentrations. Lithium did not affect AQP2 stability but decreased its mRNA levels. Surprising, the effect of lithium was cAMP independent; it did not alter AVP-stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or cAMP responsive element binding protein. In vivo, kidney tissue of rats with lithium-induced NDI indeed generated less dDAVP-induced cAMP than that of controls, but this could be due to elevated blood AVP levels in rats with lithium-induced NDI. Indeed, Brattleboro rats, which lack endogenous AVP, with clamped blood dDAVP levels, showed no difference in dDAVP-generated cAMP generation between kidneys of rats with lithium-induced NDI and control rats. In conclusion, the first proper cell model to study lithium-induced NDI was developed, and it was demonstrated that the lithium-induced downregulation of AQP2 and development of NDI occur independent of adenylyl cyclase activity in vitro and in vivo.

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

“…Thus, it is plausible that lithium treatment further results in translocation of ␤-catenin to the IMCD cell nucleus, where it can regulate transcription of target genes. A previous study has reported that the effect of lithium on AQP2 down-regulation is mediated by a transcriptional mechanism (23). Interestingly, using bioinformatics we discovered that both the mouse and rat AQP2 gene 5Ј flanking regions contain several consensus sites for TCF, thus AQP2 gene transcription may be regulated directly by TCF-dependent transcription.…”

Diabetes Insipidus: A Review

“…Lithium's mechanism in causing NDI is unknown and a variety of mechanisms have been proposed -one of which is by decreasing cellular cAMP, causing decreased insertion of AQP2 into the apical membrane [83,84]. Other research shows that lithium's action is likely not due to cAMP, but rather, to AQP2 transcription reduction and AQP2 mRNA degradation [85]. Another proposed method of decreased aquaporin 2 insertion is via lithium's inhibition of glycogen synthase kinase 3 (GSK-3), one of the regulatory enzymes of AQP2 and epithelial sodium channels (ENaC's).…”

Lithium-induced Nephrogenic Diabetes Insipidus and Renal Failure: A Case Report

“…Kronik lityum kullanımında NDİ, hastaların % 20-40'ında görülebilir (2,8,9). Hastamızda kronik lityum kullanımına bağlı NDİ vardı.…”