Prasugrel Suppresses Development of Lithium‐induced Nephrogenic Diabetes Insipidus in Mice

Previously we localized ADP‐activated P2Y 12 receptor in rodent kidney and showed that its blockade by clopidogrel bisulfate (CLPD) attenuates lithium(Li)‐induced nephrogenic diabetes insipidus (NDI) (Zhang et al, JASN ePub 2015; Zhang et al, Puriner Signal ePub 2015). In order to explore whether such attenuation is possible by the use of other drugs that are known to block P2Y 12 receptor, we evaluated the effect of administration of prasugrel (PRSG) on Li‐induced NDI in mice. Similar to CLPD, PRSG belongs to thienopyridine class of ADP receptors inhibitors, and is a prodrug metabolized in the liver into its active form, which irreversibly binds to P2Y 12 receptor. Groups of age‐matched adult B6D2 mice (n = 5/group) were fed either regular rodent chow (controls, CNT) or rodent chow with added LiCl (LI; 40 mmol/kg chow) or PRSG in drinking water (PRG; 10 mg/kg bw/day) or a combination of Li and PRSG for 14 days. Twenty‐four hour water consumption and urine output were determined on day 0 and day 14, and the mice were humanely euthanized. Blood and kidney tissues were collected and analyzed. Administration of PRSG completely suppressed Li‐induced NDI as assessed by water intake, urine output and urine osmolality. Semi‐quantitative immunoblotting revealed that administration of PRSG significantly prevented Li‐induced decrease in AQP2 protein abundance in renal cortex (3.4‐fold higher) and medulla (3.2‐fold higher). Serum Li, Na, and K levels and osmolality were not affected by the administration of PRG. Similar to CLPD, PRSG administration had no effect on Li‐induced increase in urinary Na excretion. Taken together, our data suggest that pharmacological inhibition of P2Y12 receptor by thienopyridine group of drugs may potentially offer therapeutic benefits in Li‐induced NDI. Support or Funding Information Dept. of Veterans Affairs