Submitted on August 4, 2007
Accepted on January 17, 2008
Treating Lithium-Induced Nephrogenic Diabetes Insipidus with a COX-2 Inhibitor Improves Polyuria via Upregulation of AQP2 and NKCC2
Gheun-Ho Kim1*, Nak Won Choi2, Ju-Young Jung3, Ji-Hyun Song3, Chang Hwa Lee1, Chong Myung Kang1, and Mark A. Knepper4
1 Internal Medicine, Hanyang University College of Medicine, Seoul, Korea, Republic of
2 Internal Medicine, Konyang University College of Medicine, Nonsan, Korea, Republic of
3 Anatomy, Chungnam National University College of Veterinary Medicine, Daejeon, Korea, Republic of
4 Laboratory of Kidney and Electrolyte Metabolism, NIH, Bethesda, Maryland, United States
* To whom correspondence should be addressed. E-mail: kimgh{at}hanyang.ac.kr.
Prostaglandin E2 may antagonize vasopressin-stimulated salt absorption in the thick ascending limb and water absorption in the collecting duct. Blockade of prostaglandin E2 synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) enhance 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 feeding male Sprague-Dawley rats LiCl-containing rat diet for 3 weeks, rats were randomly divided into control and experimental groups. The COX-2 inhibitor, DFU (40 mg/kg/d), 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.
