TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction.
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.
Meldrum
K K
KK
Department of Urology, Indiana University, Indianapolis, IN 46202, USA. kmeldrum@iupui.edu
Misseri
R
R
Metcalfe
P
P
Dinarello
C A
CA
Hile
K L
KL
Meldrum
D R
DR
D000199:Actins / Q000096:biosynthesis; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000235:genetics; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D006207:Half-Life; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology*; D007700:Kinetics; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012995:Solubility; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*; D014513:Ureter / Q000601:surgery; D014517:Ureteral Obstruction / Q000150:complications* / Q000209:etiology / Q000473:pathology*
D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; D024141:Collagen Type IV; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; C506237:Tnfrsf1a protein, rat; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000808:Angiotensinogen; D011092:Polyethylene Glycols