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Am J Physiol Regul Integr Comp Physiol 292: R1456-R1464, 2007. First published December 14, 2006; doi:10.1152/ajpregu.00620.2005
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INFLAMMATION AND CYTOKINES

TNF- neutralization ameliorates obstruction-induced renal fibrosis and dysfunction

Departments of ¹Urology and ³Surgery, Indiana University, Indianapolis, Indiana; and the ²Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 25 August 2005 ; accepted in final form 7 December 2006

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- 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- expression (ELISA), macrophage infiltration (ED-1 staining), transforming growth factor-₁ expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, immunohistochemistry), -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- and transforming growth factor-₁ levels, collagen I and IV activity, interstitial volume, -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- mediates obstruction-induced renal fibrosis and identify TNF- neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

kidney; glomerular filtration rate; cytokine; smooth muscle actin; transforming growth factor

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