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.