title: Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice.
abstract: Previously, we localized ADP-activated P2Y12receptor (R) in rodent kidney and showed that its blockade by clopidogrel bisulfate (CLPD) attenuates lithium (Li)-induced nephrogenic diabetes insipidus (NDI). Here, we evaluated the effect of prasugrel (PRSG) administration on Li-induced NDI in mice. Both CLPD and PRSG belong to the thienopyridine class of ADP receptor antagonists. Groups of age-matched adult male B6D2 mice (N = 5/group) were fed either regular rodent chow (CNT), or with added LiCl (40 mmol/kg chow) or PRSG in drinking water (10 mg/kg bw/day) or a combination of LiCl and PRSG for 14 days and then euthanized. Water intake and urine output were determined and blood and kidney tissues were collected and analyzed. PRSG administration completely suppressed Li-induced polydipsia and polyuria and significantly prevented Li-induced decreases in AQP2 protein abundance in renal cortex and medulla. However, PRSG either alone or in combination with Li did not have a significant effect on the protein abundances of NKCC2 or NCC in the cortex and/or medulla. Immunofluorescence microscopy revealed that PRSG administration prevented Li-induced alterations in cellular disposition of AQP2 protein in medullary collecting ducts. Serum Li, Na, and osmolality were not affected by the administration of PRSG. Similar to CLPD, PRSG administration had no effect on Li-induced increase in urinary Na excretion. However, unlike CLPD, PRSG did not augment Li-induced increase in urinary arginine vasopressin (AVP) excretion. Taken together, these data suggest that the pharmacological inhibition of P2Y12-R by the thienopyridine group of drugs may potentially offer therapeutic benefits in 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: Anna U
authors.initials: AU
authors.lastname: Brandes
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: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Carlson
authors.affiliation: Depatment of Neurobiology and Anatomy and Center on Aging, University of Utah Health Sciences Center, Geriatric Research, Education, and Clinical Center (GRECC) Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive (151B), Salt Lake City, UT, 84148, USA.
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: D000818:Animals; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced*; D007668:Kidney / Q000187:drug effects*; D018021:Lithium Chloride / Q000633:toxicity*; D008297:Male; D051379:Mice; D000068799:Prasugrel Hydrochloride / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D018021:Lithium Chloride; D000068799:Prasugrel Hydrochloride
keywords: Arginine vasopressin; Diabetes insipidus; Extracellular nucleotides; Nephrogenic; Polyuria; Purinergic receptors