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Original Report: Laboratory Investigation

Neutralization of Tumor Necrosis Factor-Alpha Reduces Renal Fibrosis and Hypertension in Rats with Renal Failure

Therrien F.J. · Agharazii M. · Lebel M. · Larivière R.

Author affiliations

Nephrology and Hypertension, CHUQ Research Centre, L’Hôtel-Dieu de Québec Hospital and Department of Medicine, Université Laval, Quebec, Que., Canada

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Am J Nephrol 2012;36:151–161

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Article / Publication Details

First-Page Preview
Abstract of Original Report: Laboratory Investigation

Received: January 25, 2012
Accepted: June 12, 2012
Published online: July 19, 2012
Issue release date: August 2012

Number of Print Pages: 11
Number of Figures: 4
Number of Tables: 6

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: https://www.karger.com/AJN

Abstract

Background: Increased production of tumor necrosis factor-α (TNF-α) in chronic kidney disease may be involved in the progression of renal failure and injury, and cardiovascular disease. We investigated the effect of TNF-α neutralization on renal failure, inflammation and fibrosis, and blood pressure in rats with renal failure. Methods and Results: Renal failure was induced by renal mass reduction and the animals were treated with PEG-sTNFR1, a pegylated form of soluble TNF type 1 receptor that neutralizes TNF-α, for 6 weeks. Systolic, diastolic and mean arterial pressures were higher in renal failure rats that were associated with increased serum creatinine, albuminuria and renal injury comprised of blood vessel media hypertrophy, focal and segmental glomerulosclerosis, tubular atrophy and interstitial inflammation and fibrosis. These changes were associated with greater levels of TNF-α, transforming growth factor (TGF)-β1, nuclear transcription factor NF-ĸB and cytosolic phospho-IĸB-α, and inflammatory markers expression (ICAM-1, VCAM-1 and MCP-1). Moreover, endothelin (ET)-1 production was also increased, whereas nitric oxide (NO) release was decreased. TNF-α neutralization reduced hypertension, albuminuria and renal inflammation and fibrosis, which were coupled to a reduction in renal NF-ĸB activation, inflammatory markers expression, TGF-β1 and ET-1 production, and an increase in NO release. Conclusion: Neutralization of TNF-α in rats with renal failure decreases NF-ĸB activity that is associated with a reduction in renal TGF-β1 and ET-1 production, and an improvement of NO release. These effects likely reduce renal inflammation and fibrosis, and blood pressure indicating a pivotal role for TNF-α, at least, in the progression of renal injury.

© 2012 S. Karger AG, Basel


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Article / Publication Details

First-Page Preview
Abstract of Original Report: Laboratory Investigation

Received: January 25, 2012
Accepted: June 12, 2012
Published online: July 19, 2012
Issue release date: August 2012

Number of Print Pages: 11
Number of Figures: 4
Number of Tables: 6

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: https://www.karger.com/AJN


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