title: Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2.
abstract: Prostaglandin E(2) may antagonize vasopressin-stimulated salt absorption in the thick ascending limb and water absorption in the collecting duct. Blockade of prostaglandin E(2) synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) enhances urinary concentration, and these agents have antidiuretic effects in patients with nephrogenic diabetes insipidus (NDI) of different etiologies. Because renal prostaglandins are derived largely from cyclooxygenase-2 (COX-2), we hypothesized that treatment of NDI with a COX-2 inhibitor may relieve polyuria through increased expression of Na-K-2Cl cotransporter type 2 (NKCC2) in the thick ascending limb and aquaporin-2 (AQP2) in the collecting duct. To test this hypothesis, semiquantitative immunoblotting and immunohistochemistry were carried out from the kidneys of lithium-induced NDI rats with and without COX-2 inhibition. After male Sprague-Dawley rats were fed an LiCl-containing rat diet for 3 wk, the rats were randomly divided into control and experimental groups. The COX-2 inhibitor DFU (40 mg.kg(-1).day(-1)) was orally administered to the experimental rats for an additional week. Treatment with the COX-2 inhibitor significantly relieved polyuria and raised urine osmolality. Semiquantitative immunoblotting using whole-kidney homogenates revealed that COX-2 inhibition caused significant increases in the abundance of AQP2 and NKCC2. Immunohistochemistry for AQP2 and NKCC2 confirmed the effects of COX-2 inhibition in lithium-induced NDI rats. The upregulation of AQP2 and NKCC2 in response to the COX-2 inhibitor may underlie the therapeutic mechanisms by which NSAIDs enhance antidiuresis in patients with NDI.
authors.affiliation: Dept. of Internal Medicine, Hanyang Univ. College of Medicine, 17 Haengdang-dong Seongdong-gu, Seoul 133-792, South Korea. kimgh@hanyang.ac.kr
authors.forename: Gheun-Ho
authors.initials: GH
authors.lastname: Kim
authors.forename: Nak Won
authors.initials: NW
authors.lastname: Choi
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Jung
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Song
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Lee
authors.forename: Chong Myung
authors.initials: CM
authors.lastname: Kang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Knepper
mesh_terms: D000818:Animals; D050034:Antidiuretic Agents / Q000627:therapeutic use*; D051399:Aquaporin 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy*; D015232:Dinoprostone / Q000378:metabolism; D005663:Furans / Q000627:therapeutic use; D008297:Male; D011141:Polyuria / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D050034:Antidiuretic Agents; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D015232:Dinoprostone