Effects of tumor necrosis factor-\u03b1 inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy

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

doi:10.1038/s41598-021-02864-1

Sho Kinguchi, Kengo Azushima + Show 11 more

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https://doi.org/10.1038/s41598-021-02864-1

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Abstract

Tumor 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.

Highlights

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD)
To investigate whether TNF-α inhibition prevents the development of kidney fibrosis, and to elucidate the underlying molecular mechanisms, we evaluated the effects of etanercept (ETN), which is a fusion protein competitively acting as a "TNF-α decoy receptor" to inhibit the binding of TNF-α to its cell surface receptor[34], on kidney functional decline, inflammation, and fibrosis in a murine model of AAN
At the start of the experimental period, there were no significant differences in body weight (BW), systolic blood pressure (BP), or heart rate (HR) among control, aristolochic acid (AA) and AA + ETN groups

Summary

Introduction

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). 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. 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. To investigate whether TNF-α inhibition prevents the development of kidney fibrosis, and to elucidate the underlying molecular mechanisms, we evaluated the effects of etanercept (ETN), which is a fusion protein competitively acting as a "TNF-α decoy receptor" to inhibit the binding of TNF-α to its cell surface receptor[34], on kidney functional decline, inflammation, and fibrosis in a murine model of AAN

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