title: NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip.
abstract: Vasopressin increases urine concentration through activation of aquaporin-2 (AQP2) in the collecting duct. Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin E2 synthesis, and may suppress AQP2 producing a urine concentrating defect. There are four serines in AQP2 that are phosphorylated by vasopressin. To determine if chronic use of NSAIDs changes AQP2's phosphorylation at any of these residues, the effects of a non-selective NSAID, ibuprofen, and a COX-2-selective NSAID, meloxicam, were investigated. Daily ibuprofen or meloxicam increased the urine output and decreased the urine osmolality significantly by days 7 through 14. Concomitantly, meloxicam significantly reduced total AQP2 protein abundance in inner medulla (IM) tip to 64% of control and base to 63%, respectively. Ibuprofen significantly decreased total AQP2 in IM tip to 70% of control, with no change in base. Meloxicam significantly increased the ratios of p256-AQP2 and p261-AQP2 to total AQP2 in IM tip (to 44% and 40%, respectively). Ibuprofen increased the ratio of p256-AQP2 to total AQP2 in IM tip but did not affect p261-AQP2/total AQP2 in tip or base. Both ibuprofen and meloxicam increased p264-AQP2 and p269-AQP2 ratios in both tip and base. Ibuprofen increased UT-A1 levels in IM tip, but not in base. We conclude that NSAIDs reduce AQP2 abundance, contributing to decreased urine concentrating ability. They also increase some phosphorylated forms of AQP2. These changes may partially compensate for the decrease in AQP2 abundance, thereby lessening the decrease in urine osmolality.
authors.affiliation: Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Molina
authors.affiliation: Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Physiology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Sands
authors.affiliation: Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Physiology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology; D051399:Aquaporin 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007052:Ibuprofen / Q000008:administration & dosage* / Q000494:pharmacology; D007671:Kidney Concentrating Ability; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D000077239:Meloxicam; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000008:administration & dosage* / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D013843:Thiazines; D013844:Thiazoles; D000077239:Meloxicam; D007052:Ibuprofen