title: P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.
abstract: P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI.
authors: Nephrology Research and Department of Internal Medicine.
authors: Yue
authors: Y
authors: Zhang
authors: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, University of Southern California, Los Angeles, California;
authors: Janos
authors: J
authors: Peti-Peterdi
authors: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany; and.
authors: Christa E
authors: CE
authors: Müller
authors: Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah; Department of Neurobiology and Anatomy, and Center on Aging, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors: Noel G
authors: NG
authors: Carlson
authors: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany; and Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
authors: Younis
authors: Y
authors: Baqi
authors: Nephrology Research and Department of Internal Medicine.
authors: David L
authors: DL
authors: Strasburg
authors: Nephrology Research and Department of Internal Medicine.
authors: Kristina M
authors: KM
authors: Heiney
authors: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, University of Southern California, Los Angeles, California;
authors: Karie
authors: K
authors: Villanueva
authors: Nephrology Research and Department of Internal Medicine.
authors: Donald E
authors: DE
authors: Kohan
authors: Nephrology Research and Department of Internal Medicine, Center on Aging, University of Utah Health Sciences Center, Salt Lake City, Utah; BK.Kishore@hsc.utah.edu.
authors: Bellamkonda K
authors: BK
authors: Kishore
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000032:analysis / Q000187:drug effects / Q000652:urine; D001127:Arginine Vasopressin / Q000187:drug effects / Q000378:metabolism* / Q000652:urine; D000077144:Clopidogrel; D003894:Deamino Arginine Vasopressin / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007679:Kidney Medulla / Q000737:chemistry; D007685:Kidney Tubules, Collecting / Q000737:chemistry / Q000378:metabolism* / Q000503:physiopathology*; D008094:Lithium; D008297:Male; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011910:Rats, Brattleboro; D017207:Rats, Sprague-Dawley; D058925:Receptors, Purinergic P2Y12 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014867:Water / Q000378:metabolism
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D058921:Purinergic P2Y Receptor Antagonists; D012333:RNA, Messenger; D058925:Receptors, Purinergic P2Y12; D014867:Water; D001127:Arginine Vasopressin; D008094:Lithium; D000077144:Clopidogrel; D003894:Deamino Arginine Vasopressin; D013988:Ticlopidine
keywords: collecting ducts; cyclic AMP; diabetes insipidus; extracellular; hypothalamus; nucleotides; vasopressin