Targeting renal purinergic signalling for the treatment of lithium‐induced nephrogenic diabetes insipidus

Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium‐induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP‐activated P2Y₂ receptor in lithium‐induced NDI in rats and showed that P2Y₂ receptor knockout mice are significantly resistant to Li‐induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP‐activated P2Y₁₂ receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix^®) ameliorates Li‐induced NDI in rodents. Parallel in vitro studies showed that P2Y₁₂ receptor blockade by the reversible antagonist PSB‐0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y₂ or P2Y₁₂ receptors to counter AVP resistance in lithium‐induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti‐AVP effects to those that enhance the sensitivity of the kidney to AVP action.