title: Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus.
abstract: 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.
authors: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Nephrology Research, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.|Center on Aging, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors: B K
authors: BK
authors: Kishore
authors: Center on Aging, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Department of Neurobiology and Anatomy, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
authors: N G
authors: NG
authors: Carlson
authors: Department of Medicine, Georgetown University, Washington, DC, USA.|Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, DC, USA.
authors: C M
authors: CM
authors: Ecelbarger
authors: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Nephrology Research, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
authors: D E
authors: DE
authors: Kohan
authors: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
authors: C E
authors: CE
authors: Müller
authors: Department of Paediatrics, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors: R D
authors: RD
authors: Nelson
authors: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA.
authors: J
authors: J
authors: Peti-Peterdi
authors: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Nephrology Research, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
authors: Y
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000378:metabolism*; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000628:therapy*; D006801:Humans; D008094:Lithium / Q000633:toxicity*; D009318:Natriuresis / Q000502:physiology; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*
chemical_list: D020346:Aquaporins; D058473:Receptors, Purinergic P2Y2; D001127:Arginine Vasopressin; D008094:Lithium
keywords: P2Y12 receptor; P2Y2 receptor; arginine vasopressin; collecting duct; prostaglandins; water channels