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

Kirstan K. Meldrum, Peter Metcalfe, Jeffrey Leslie, Rosalia Misseri, Karen L. Hile, Daniel R. Meldrum

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Background. Obstruction 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 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-α expression (ELISA), NFκB activation (EMSA, immunohistochemistry), IκB degradation (Western blot), angiotensinogen expression (Western blot), and apoptosis (TUNEL). Results. Renal 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. Conclusion. TNF-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.

Original languageEnglish (US)
Pages (from-to)182-188
Number of pages7
JournalJournal of Surgical Research
Volume131
Issue number2
DOIs
StatePublished - Apr 2006
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Apoptosis
Kidney
Angiotensinogen
Western Blotting
Ureteral Obstruction
Tumor Necrosis Factor Receptors
In Situ Nick-End Labeling
Wounds and Injuries
Urinary Tract
Ambulatory Surgical Procedures
Sprague Dawley Rats
Cell Death
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Phosphorylation

Keywords

  • Angiotensin
  • Cytokines
  • Inflammation
  • Kidney
  • Transcription

ASJC Scopus subject areas

  • Surgery

Cite this

Meldrum, K. K., Metcalfe, P., Leslie, J., Misseri, R., Hile, K. L., & Meldrum, D. R. (2006). TNF-α neutralization decreases nuclear factor-κB activation and apoptosis during renal obstruction. Journal of Surgical Research, 131(2), 182-188. https://doi.org/10.1016/j.jss.2005.11.581

TNF-α neutralization decreases nuclear factor-κB activation and apoptosis during renal obstruction. / Meldrum, Kirstan K.; Metcalfe, Peter; Leslie, Jeffrey; Misseri, Rosalia; Hile, Karen L.; Meldrum, Daniel R.

In: Journal of Surgical Research, Vol. 131, No. 2, 04.2006, p. 182-188.

Research output: Contribution to journalArticle

Meldrum, KK, Metcalfe, P, Leslie, J, Misseri, R, Hile, KL & Meldrum, DR 2006, 'TNF-α neutralization decreases nuclear factor-κB activation and apoptosis during renal obstruction', Journal of Surgical Research, vol. 131, no. 2, pp. 182-188. https://doi.org/10.1016/j.jss.2005.11.581
Meldrum, Kirstan K. ; Metcalfe, Peter ; Leslie, Jeffrey ; Misseri, Rosalia ; Hile, Karen L. ; Meldrum, Daniel R. / TNF-α neutralization decreases nuclear factor-κB activation and apoptosis during renal obstruction. In: Journal of Surgical Research. 2006 ; Vol. 131, No. 2. pp. 182-188.
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AB - Background. Obstruction 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 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-α expression (ELISA), NFκB activation (EMSA, immunohistochemistry), IκB degradation (Western blot), angiotensinogen expression (Western blot), and apoptosis (TUNEL). Results. Renal 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. Conclusion. TNF-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.

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