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.

Severe toxicity and cyclooxygenase (COX)-2 mRNA increase by lithium in the neonatal mouse kidney

“…Second, induction of COX-2 by lactational exposure to TCDD, a polychlorinated polycyclic aromatic hydrocarbon, was shown to induce hydronephrosis in the neonate of rodents, but the administration of a selective inhibitor to COX-2 abolished such a pathogenesis (Nishimura et al, 2008). Our present study showed that LiCl injection induces an increase in COX-2 mRNA and an associated decrease in AQP2 mRNA (Norregaard et al, 2007;Kim et al, 2008) in the neonatal kidney (Fig. 2) and resulted in severe histopathological alterations leading to hydronephrosis.…”

“…Potassium concentra--tion (Table 2). It has been reported that lithium administration affects kidney functions including diuresis in a COX-2-mediated manner (Rao et al, 2005), and that COX-2 negatively regulates gene expression of water channels such as AQPs 2 and 3, and transporters such as Na-K-2Cl cotransporter type 2 (NKCC2), in the kidney (Kim et al, 2008;Norregaard et al, 2007). In this context, we quantified mRNA of COX-2, AQP2, AQP3, and NKCC2 in the kidney from LiCl-injected mice and control mice on PND 7.…”

“…To this end, we selected a lithium compound as a test chemical by the following reasons. First, lithium has been reported to induce COX-2 in vivo (Rao et al, 2005;Kim et al, 2008) and in vitro (Rao et al, 2004), but no detailed analysis has been performed on the pathogenesis of hydronephrosis. Second, lithium is an important therapeutic drug for treatment of mood disorder and Alzheimer's disease (Eldar-Finkelman, 2002;Luna-Medina et al, 2005;Woodgett, 2001) and has been routinely prescribed in a clinical practice.…”

Lithium in the Kidney: Friend and Foe?

“…[60][61][62] PGE2 activates the EP3 receptor in principal cells, leading to a reduced cAMP signaling, AQP2 expression, and plasma membrane targeting. 48,63 Importantly, renal PGE2 production is stimulated by flow-stimulated release of ATP and its degradation products by activation of their P2Y receptors.…”

Diabetes insipidus: the basic and clinical review

“…[66][67][68][69] Prostaglandin synthase inhibitors are used because they increase the AQP-2 channels at apical membrane by increasing intracellular cAMP level. 70,71 The main side effect of these drugs is that they cause kidney damage and gastric problems. 11,72,73 Recent studies have shown that long term treatment with thiazides can cause renal carcinoma.…”