Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy

Author:

Taguchi Shinya,Azushima Kengo,Yamaji Takahiro,Urate Shingo,Suzuki Toru,Abe Eriko,Tanaka Shohei,Tsukamoto Shunichiro,Kamimura Daisuke,Kinguchi Sho,Yamashita Akio,Wakui Hiromichi,Tamura Kouichi

Abstract

AbstractTumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

Funder

Uehara Memorial Foundation

Yokohama Foundation for Advancement of Medical Science

Japan Society for the Promotion of Science

Japanese Association of Dialysis Physicians

Japan Kidney Association-Nippon Boehringer Ingelheim Joint Research Program

Salt Science Research Foundation

Strategic Research Project of Yokohama City University

Japan Agency for Medical Research and Development

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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