TNF-α Neutralization Decreases Nuclear Factor-κB Activation and Apoptosis During Renal Obstruction 1

BackgroundObstruction of the upper urinary tract is an important cause of progressive renal injury in children. While tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) have independently been implicated in the pathophysiology of this process, TNF-α’s role in obstruction-induced NFκB activation has not previously been investigated.Materials and methodsTo 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-α expression (ELISA), NFκB activation (EMSA, immunohistochemistry), IκB degradation (Western blot), angiotensinogen expression (Western blot), and apoptosis (TUNEL).ResultsRenal cortical TNF-α levels, NFκB activation, IκB degradation, angiotensinogen expression, and apoptotic cell death were significantly increased in response to obstruction. In contrast, TNF-α neutralization significantly reduced obstruction-induced TNF-α production, NFκB activation, IκB degradation, angiotensinogen expression, and renal tubular cell apoptosis.ConclusionTNF-α’s potent pro-inflammatory and cytotoxic effect during renal obstruction is directed through NFκB activation via increased IκB-α phosphorylation. As the role of TNF-α and NFκB in renal obstruction are further defined, the development of therapeutic strategies that limit or prevent obstruction-induced renal injury may be realized.