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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 292; no. 4; p. R1456
• Main Authors: Meldrum, K K, Misseri, R, Metcalfe, P, Dinarello, C A, Hile, K L, Meldrum, D R
• Format: Journal Article
• Language: English
• Published: United States 01-04-2007
• Subjects: 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
• ISSN: 0363-6119
• DOI: 10.1152/ajpregu.00620.2005

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.