TNF-alpha neutralization decreases nuclear factor-kappaB activation and apoptosis during renal obstruction.

Abstract

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 kappaB (NFkappaB) have independently been implicated in the pathophysiology of this process, TNF-alpha's role in obstruction-induced NFkappaB 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), NFkappaB activation (EMSA, immunohistochemistry), IkappaB degradation (Western blot), angiotensinogen expression (Western blot), and apoptosis (TUNEL).

RESULTS:

Renal cortical TNF-alpha levels, NFkappaB activation, IkappaB 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, NFkappaB activation, IkappaB degradation, angiotensinogen expression, and renal tubular cell apoptosis.

CONCLUSION:

TNF-alpha's potent pro-inflammatory and cytotoxic effect during renal obstruction is directed through NFkappaB activation via increased IkappaB-alpha phosphorylation. As the role of TNF-alpha and NFkappaB in renal obstruction are further defined, the development of therapeutic strategies that limit or prevent obstruction-induced renal injury may be realized.

• Authors: Kirstan K Meldrum, Peter Metcalfe, Jeffrey A Leslie, Rosalia Misseri, Karen L Hile, Daniel R Meldrum
• Journal: The Journal of surgical research (J Surg Res) Vol. 131 Issue 2 Pg. 182-8 (Apr 2006) ISSN: 0022-4804 [Print] United States
• PMID: 16412467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• I-kappa B Proteins
• NF-kappa B
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Apoptosis
• Child
• Enzyme-Linked Immunosorbent Assay
• Humans
• I-kappa B Proteins (metabolism)
• Immunohistochemistry
• Inflammation
• Kidney Diseases (physiopathology)
• Male
• NF-kappa B (physiology)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Tumor Necrosis Factor-alpha (biosynthesis, physiology)
• Urethral Obstruction (physiopathology)