Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus

Abstract

Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.

Evidence for a regulated Ca2+ entry in proximal tubular cells and its implication in calcium stone formation

“…6G). Such a difference in enhanced Li + excretion in KO mice started to display late (after 72 h) and could be due to adaptability to Li + treatment, which is typical and has been shown for other mice urine measurements such as urine volume, urine osmolarity (Huls et al, 2007) (Sim et al, 2014). The absence of TRPC3 in our animal model was confirmed via further immunofluorescence staining (Fig.…”

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

“…For example, several previous studies implicating a role for reduced cAMP in the onset of Li-NDI did not measure cAMP levels in vivo (12,36), whereas a direct cause-effect correlation cannot be concluded from other models with diminished cAMP levels following Li + treatment (17) due to compensatory mechanisms, such as a negative-feedback response of cells to increased AVP levels (37). A strength of the current study was the use two different mouse models that lack AC6, the AC isoform mediating the majority of AVP-induced IM cAMP formation, allowing us to assess directly a role of cAMP in Li-NDI.…”

“…However, despite major progress, no clear consensus regarding the "trigger" for the onset of the condition exists. For example, data from large-scale proteomic (7) and metabonomic approaches (8), coupled with targeted studies in animal models and gene-modified mice, have illustrated changes in renal prostaglandins (9); purinergic signaling (10); and the activity of glycogen synthase kinase 3 (GSK3) (11), PKC (12), MAPKs, ERKs ERK1/2 and P38α (13), and the phosphatidylinositol signalPsychiatric patients treated with lithium (Li + ) may develop nephrogenic diabetes insipidus (NDI). Although the etiology of Li + -induced NDI (Li-NDI) is poorly understood, it occurs partially due to reduced aquaporin-2 (AQP2) expression in the kidney collecting ducts.…”

The Trafficking of the Water Channel Aquaporin-2 in Renal Principal Cells—a Potential Target for Pharmacological Intervention in Cardiovascular Diseases

“…One of the main causes is the long-term treatment of bipolar disorders with lithium. This causes acquired NDI in up to 40% of the patients (Sim et al, 2014 ). In elderly patients a 6-year prevalence rate of 3% was observed (Rej et al, 2014 ).…”