Treatmenting lithium-induced nephrogenic diabetes insipidus with the COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2

Abstract

Prostaglandin E2 may antagonize vasopressin-stimulated salt absorption in the thick ascending limb (TAL) and water absorption in the collecting duct (CD). Blockade of prostaglandin E2 synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) enhance urinary concentration, and these agents have antidiuretic effect in patients with nephrogenic diabetes insipidus (NDI) of different etiologies. Because the renal effects of prostaglandins are derived from cyclooxygenase-2 (COX-2), we hypothesized that treatment of NDI with the COX-2 inhibitor may relieve polyuria through upregulation of Na-K-2Cl cotransporter type 2 (NKCC2) in the TAL and aquaporin-2 (AQP2) in the CD. 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 relieved polyuria (68 ± 10 vs. 134 ± 15 mL/d, P<0.05) and raised urine osmolality (402 ± 51 vs. 247 ± 40 mOsm/kg H2O, P<0.05). However, urinary excretion of sodium and chloride were not affected by the treatment. Semiquantitative immunoblotting using whole-kidney homogenates revealed that COX-2 inhibition caused significant increases in the abundance of AQP2 (219 ± 9 vs. 100 ± 22%, P<0.01) and NKCC2 (186 ± 30 vs. 100 ± 14%, P<0.05). 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.