Genetic deletion of ADP-activated P2Y12 receptor ameliorates lithium-induced nephrogenic diabetes insipidus in mice

Abstract

Aim: Therapeutic use of lithium in bipolar disorder is limited by the development of nephrogenic diabetes insipidus (NDI). We reported that pharmacological blockade of P2Y₁₂ receptor (R) with clopidogrel or prasugrel significantly ameliorated lithium-induced NDI in rodents. Using mice genetically lacking P2Y₁₂ -R we evaluated whether the observed amelioration is mediated through P2Y₁₂ -R METHODS: P2ry12^-/- mouse line (C57/BL6) was rederived from cryopreserved embryos of the knockout (KO) mice generated by Deltagen Inc. Syngeneic wild type (WT) mice obtained by heterozygous crossing were inbred. Groups of adult WT and KO mice were fed lithium-added (40 mmol LiCl/kg food) or regular diet, and euthanized after 2 or 4 weeks. Twenty-four hour urine samples and terminal blood and kidney samples were analyzed.

Results: At both time points, lithium-induced polyuria and decrease in aquaporin-2 (AQP2) protein abundance in the kidney medulla were less marked in KO vs WT mice. Immunofluorescence microscopy revealed that lithium-induced alterations in the cellular disposition of AQP2 protein in the medullary collecting ducts of WT mice were blunted in KO mice. Serum lithium, sodium and osmolality were similar in both genotypes after lithium treatment. After 2 weeks, lithium induced marked increases in urinary excretion of Na, K, and arginine vasopressin in WT mice but not in KO mice.

Conclusion: Taken together, our data show that similar to pharmacological blockade, deletion of P2Y₁₂ -R significantly ameliorates lithium-induced NDI, without reducing serum lithium levels. Hence, targeting P2Y₁₂ -R with currently available drugs in the market offers a novel and safer method for treating NDI.

Keywords: P2Y12 receptor; P2Y2 receptor; arginine vasopressin; collecting duct; diabetes insipidus; lithium.