Research Papers:

Inhibition of tumor necrosis factor signaling attenuates renal immune cell infiltration in experimental membranous nephropathy

Yen-Sung Huang, Shin-Huei Fu, Kuo-Cheng Lu, Jin-Shuen Chen, Hsin-Yi Hsieh, Huey-Kang Sytwu and Chia-Chao Wu _

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Oncotarget. 2017; 8:111631-111641. https://doi.org/10.18632/oncotarget.22881

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Yen-Sung Huang1, Shin-Huei Fu2, Kuo-Cheng Lu3,4, Jin-Shuen Chen3, Hsin-Yi Hsieh2, Huey-Kang Sytwu2 and Chia-Chao Wu2,3

1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

2Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan

3Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

4Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei City, Taiwan

Correspondence to:

Chia-Chao Wu, email: [email protected]

Keywords: tumor necrosis factor; membranous nephropathy; etanercept; preligand assembly domain; immunomodulation

Received: July 25, 2017     Accepted: November 23, 2017     Published: December 04, 2017


Idiopathic membranous nephropathy (MN) is an autoimmune-mediated glomerulonephritis and the most common cause of idiopathic nephrotic syndrome in adult humans. A tumor necrosis factor α (TNF-α)-mediated inflammatory response via TNF receptor 1 (TNFR1) and TNFR2 has been proposed as a pathogenic factor. In this study, we assessed the therapeutic response to blocking TNF signaling in experimental MN. Murine MN was induced experimentally by cationic bovine serum albumin (cBSA); phosphate-buffered saline was used in control mice. In MN mice, TNF was inhibited by etanercept blocking of TNFR1/TNFR2 or the preligand assembly domain fusion protein (PLAD.Fc), a small fusion protein that can preferentially block TNFR1 signaling. Disease severity and possible mechanisms were assessed by analyzing the metabolic and histopathology profiles, lymphocyte subsets, immunoglobulin production, oxidative stress, and apoptosis. cBSA-induced MN mice exhibited typical nephrotic syndrome and renal histopathology. MN mice given etanercept or PLAD.Fc did not exhibit significant reduction of proteinuria, amelioration of glomerular lesions, or attenuation of immune complex deposition. Immune cell subsets, serum immunoglobulin levels, production of reactive oxygen species, and cell apoptosis in the kidney were not altered by TNF inhibition. By contrast, MN mice receiving etanercept or PLAD.Fc exhibited significantly decreased infiltration of immune cells into the kidney. These results show that the therapeutic effects of blocking TNFR1 and/or TNFR2 signaling in experimental MN are not clinically effective. However, TNF signaling inhibition significantly attenuated renal immune cell infiltration in experimental MN.

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