TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction

Am J Physiol Regul Integr Comp Physiol. 2007 Apr;292(4):R1456-64. doi: 10.1152/ajpregu.00620.2005. Epub 2006 Dec 14.

Abstract

Upper urinary tract obstruction results in tubulointerstitial fibrosis and a progressive decline in renal function. Although several inflammatory mediators have been implicated in the pathophysiology of renal obstruction, the contribution of TNF-alpha to obstruction-induced fibrosis and renal dysfunction has not been thoroughly evaluated. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1) every 84 h. The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were analyzed for TNF-alpha expression (ELISA), macrophage infiltration (ED-1 staining), transforming growth factor-beta(1) expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, immunohistochemistry), alpha-smooth muscle actin accumulation (immunohistochemistry, Western blot analysis), and angiotensinogen expression (Western blot). In a separate arm, the glomerular filtration rate (inulin clearance) of rats subjected to unilateral ureteral obstruction in the presence of either vehicle or PEG-sTNFR1 was determined. Renal obstruction induced increased tissue TNF-alpha and transforming growth factor-beta(1) levels, collagen I and IV activity, interstitial volume, alpha-smooth muscle actin accumulation, angiotensinogen expression, and renal dysfunction, whereas treatment with PEG-sTNFR1 significantly reduced each of these markers of renal fibrosis. These results demonstrate that TNF-alpha mediates obstruction-induced renal fibrosis and identify TNF-alpha neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / biosynthesis
  • Angiotensinogen / metabolism
  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Collagen Type I / metabolism
  • Collagen Type IV / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Escherichia coli / genetics
  • Fibrosis / etiology
  • Fibrosis / pathology
  • Half-Life
  • Immunohistochemistry
  • Kidney Cortex / cytology
  • Kidney Cortex / immunology
  • Kidney Cortex / metabolism
  • Kidney Diseases / etiology
  • Kidney Diseases / pathology*
  • Kinetics
  • Macrophages / metabolism
  • Male
  • Molecular Weight
  • Polyethylene Glycols / chemistry
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor, Type I / chemistry
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / pharmacology*
  • Receptors, Tumor Necrosis Factor, Type I / therapeutic use
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Solubility
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ureter / surgery
  • Ureteral Obstruction / complications*
  • Ureteral Obstruction / etiology
  • Ureteral Obstruction / pathology*

Substances

  • Actins
  • Biomarkers
  • Collagen Type I
  • Collagen Type IV
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins
  • Tnfrsf1a protein, rat
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Angiotensinogen
  • Polyethylene Glycols