TNF-α neutralization decreases nuclear factor-κB activation and apoptosis during renal obstruction'

Background. Obstruction of the upper urinary tract is an important cause of progressive renal injury in children. While tumor necrosis factor-alpha (TNF-alpha) and nuclear factor kappa B (NF kappa B) have independently been implicated in the pathophysiology of this process, TNF-alpha's role in obstruction-induced NF kappa B activation has not previously been investigated. Materials and methods. To study this, male Sprague Dawley rats were subjected to 3 days of unilateral ureteral obstruction (UUO) versus sham operation. Twenty-four hours prior to surgery and 2 days after, rats received either a vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1). The kidneys were harvested 3 days postoperatively, and tissue samples were analyzed for TNF-alpha expression (ELISA), NF kappa B activation (EMSA, immunohistochemistry), I kappa B degradation (Western blot), angiotensinogen expression (Western blot), and apoptosis (TUNEL). Results. Renal cortical TNF-alpha levels, NF kappa B activation, I kappa B degradation, angiotensinogen expression, and apoptotic cell death were significantly increased in response to obstruction. In contrast, TNF-alpha neutralization significantly reduced obstruction-induced TNF-alpha production, NF kappa B activation, I kappa B degradation, angiotensinogen expression, and renal tubular cell apoptosis. Conclusion. TNF-alpha's potent pro-inflammatory and cytotoxic effect during renal obstruction is directed through NF kappa B activation via increased I kappa B-alpha phosphorylation. As the role of TNF-alpha and NF kappa B in renal obstruction are further defined, the development of therapeutic strategies that limit or prevent obstruction-induced renal injury may be realized. (C) 2006 Elsevier Inc. All rights reserved.