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However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (<jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content>), a debilitating condition. Lithium\u2010induced <jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content> is due to resistance of the kidney to arginine vasopressin (<jats:styled-content style=\"fixed-case\">AVP<\/jats:styled-content>), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">UTP<\/jats:styled-content>), acting via P2Y receptors, opposes the action of <jats:styled-content style=\"fixed-case\">AVP<\/jats:styled-content> on renal collecting duct (<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>) by decreasing the cellular <jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content> and thus <jats:styled-content style=\"fixed-case\">AQP<\/jats:styled-content>2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">UTP<\/jats:styled-content>\u2010activated P2Y<jats:sub>2<\/jats:sub> receptor in lithium\u2010induced <jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content> in rats and showed that P2Y<jats:sub>2<\/jats:sub> receptor knockout mice are significantly resistant to Li\u2010induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that <jats:styled-content style=\"fixed-case\">ADP<\/jats:styled-content>\u2010activated P2Y<jats:sub>12<\/jats:sub> receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix<jats:sup>\u00ae<\/jats:sup>) ameliorates Li\u2010induced <jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content> in rodents. Parallel <jats:italic>in\u00a0vitro<\/jats:italic> studies showed that P2Y<jats:sub>12<\/jats:sub> receptor blockade by the reversible antagonist <jats:styled-content style=\"fixed-case\">PSB<\/jats:styled-content>\u20100739 sensitizes <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content> to the action of <jats:styled-content style=\"fixed-case\">AVP<\/jats:styled-content>. Thus, our studies unravelled the potential beneficial effects of targeting P2Y<jats:sub>2<\/jats:sub> or P2Y<jats:sub>12<\/jats:sub> receptors to counter <jats:styled-content style=\"fixed-case\">AVP<\/jats:styled-content> resistance in lithium\u2010induced <jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content>. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of <jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content> by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti\u2010<jats:styled-content style=\"fixed-case\">AVP<\/jats:styled-content> effects to those that enhance the sensitivity of the kidney to <jats:styled-content style=\"fixed-case\">AVP<\/jats:styled-content> action.<\/jats:p>","DOI":"10.1111\/apha.12507","type":"journal-article","created":{"date-parts":[[2015,4,15]],"date-time":"2015-04-15T17:06:25Z","timestamp":1429117585000},"page":"176-188","source":"Crossref","is-referenced-by-count":31,"title":["Targeting renal purinergic signalling for the treatment of lithium\u2010induced nephrogenic diabetes insipidus"],"prefix":"10.1111","volume":"214","author":[{"given":"B. 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