title: Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.
abstract: Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y(12) receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25-130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y(12)-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y(12)-R may represent a novel therapeutic target for Li-induced NDI.
authors.affiliation: Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center & Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, University of Southern California, 1501 San Pablo Street, ZNI 313, Los Angeles, CA, 90033, USA.
authors.forename: János
authors.initials: J
authors.lastname: Peti-Peterdi
authors.affiliation: Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center & Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Heiney
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, University of Southern California, 1501 San Pablo Street, ZNI 313, Los Angeles, CA, 90033, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Riquier-Brison
authors.affiliation: Department of Neurobiology and Anatomy and Center on Aging Geriatric Research, Education, and Clinical Center (GRECC), University of Utah Health Sciences Center & Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive (151B), Salt Lake City, UT, 84148, USA.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Carlson
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Department of Medicine, Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, 4000 Reservoir Road NW Bldg D, Rm 392, Washington, DC, 20057, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Ecelbarger
authors.affiliation: Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center & Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA. BK.Kishore@hsc.utah.edu.
authors.forename: Bellamkonda K
authors.initials: BK
authors.lastname: Kishore
mesh_terms: D000450:Aldosterone / Q000652:urine; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D020346:Aquaporins / Q000378:metabolism; D001127:Arginine Vasopressin / Q000652:urine; D001834:Body Water / Q000378:metabolism*; D000077144:Clopidogrel; D015232:Dinoprostone / Q000652:urine; D053503:Epithelial Sodium Channels / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011141:Polyuria / Q000139:chemically induced / Q000188:drug therapy; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D020346:Aquaporins; D053503:Epithelial Sodium Channels; D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12; C578715:Slc12a1 protein, mouse; D015222:Sodium Channels; D064466:Solute Carrier Family 12, Member 1; D001127:Arginine Vasopressin; D000450:Aldosterone; D008094:Lithium; D000077144:Clopidogrel; D015232:Dinoprostone; D013988:Ticlopidine
keywords: Arginine vasopressin; Desmopressin; Diabetes insipidus; Extracellular nucleotides; Nephrogenic; Polyuria; Purinergic receptors