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Kidney Week

Abstract: PO2458

Functional Role of Tumor Necrosis Factor α Pathway in Aristolochic Acid-Induced Kidney Injury Model

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Taguchi, Shinya, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Azushima, Kengo, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Wakui, Hiromichi, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Yamaji, Takahiro, Duke-NUS Medical School, Singapore, Singapore
  • Urate, Shingo, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Suzuki, Toru, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Abe, Eriko, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Tanaka, Shohei, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Tsukamoto, Shunichiro, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Tamura, Kouichi, Yokohama City University Graduate School of Medicine Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
Background

Tumor necrosis factor (TNF)-α is a potent mediator of inflammatory responses and is suggested to be involved in the pathogenesis of kidney injuries. However, little is known about modulating effects of TNF-α inhibition on the development of kidney fibrosis. The aim of this study is to examine the effects of TNF-α inhibition on kidney inflammation and fibrosis in a mouse model of chronic kidney disease (CKD) with fibrosis.

Methods

Aristolochic acid nephropathy (AAN) was employed as the mouse model of CKD with fibrosis. To induce AAN, C57BL/6J mice were intraperitoneally administered 3 mg/kg AA twice a week followed by 4-week remodeling period. Meanwhile, 5 mg/kg etanercept (ETN) or saline were subcutaneously administered twice a week for a total of 8 weeks. At the end of experimental period, 24-hour urine samples were collected in metabolic cages, and then kidneys and blood samples were collected.

Results

TNF-α inhibition by ETN partially but significantly attenuated kidney fibrosis estimated by the picrosirius red staining, and ameliorated albuminuria without affecting kidney function in the AAN model. Treatment with ETN significantly suppressed an AA-induced increase in kidney expression of pro-inflammatory cytokines and fibrosis-related genes, including IL-1b, IL-6, type I and III collagen. Moreover, the TNF-α inhibition tended to reduce an AA-induced increase in renal interstitial TUNEL positive cells along with the suppression of kidney Bax mRNA expression. Although the kidney phosphorylated-p38 MAPK, a key mediator activated by TNF-α, was significantly up-regulated by the AA administration, this pathological up-regulation was ameliorated upon the TNF-α inhibition by ETN.

Conclusion

TNF-α inhibition by ETN significantly attenuated the development of albuminuria and kidney fibrosis, concomitant with suppression of kidney inflammation and interstitial cell apoptosis in the mouse model of CKD with fibrosis. These findings indicate that the TNF-α pathway plays a role in the pathogenesis of kidney fibrosis, and further suggest that TNF-α inhibition could become an adjunct therapeutic strategy to treat CKD.