Effects of tumor necrosis factor-α on podocyte expression of monocyte chemoattractant protein-1 and in diabetic nephropathy

Choon Hee Chung, Jingyi Fan, Eun Young Lee, Jeong Suk Kang, Seung Joo Lee, Petr E. Pyagay, Charbel C. Khoury, Tet Kin Yeo, Mark F. Khayat, Amy Wang, Sheldon Chen

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Abstract

Background/Aims: Tumor necrosis factor (TNF)-α is believed to play a role in diabetic kidney disease. This study explores the specific effects of TNF-α with regard to nephropathy-relevant parameters in the podocyte. Methods: Cultured mouse podocytes were treated with recombinant TNF-α and assayed for production of monocyte chemoattractant protein-1 (MCP-1) by enzyme-linked immunosorbent assay (ELISA). TNF-α signaling of MCP-1 was elucidated by antibodies against TNF receptor (TNFR) 1 or TNFR2 or inhibitors of nuclear factor-kappaB (NF-κB), phosphatidylinositol 3-kinase (PI3K) or Akt. In vivo studies were done on male db/m and type 2 diabetic db/db mice. Levels of TNF- α and MCP-1 were measured by RT-qPCR and ELISA in the urine, kidney and plasma of the two cohorts and correlated with albuminuria. Results: Podocytes treated with TNF-α showed a robust increase (∼900%) in the secretion of MCP-1, induced in a dose- and time-dependent manner. Signaling of MCP-1 expression occurred through TNFR2, which was inducible by TNF-α ligand, but did not depend on TNFR1. TNF-α then proceeded via the NF-κB and the PI3K/Akt systems, based on the effectiveness of the inhibitors of those pathways. For in vivo relevance to diabetic kidney disease, TNF-α and MCP-1 levels were found to be elevated in the urine of db/db mice but not in the plasma. Conclusion: TNF-α potently stimulates podocytes to produce MCP-1, utilizing the TNFR2 receptor and the NF-κB and PI3K/Akt pathways. Both TNF-α and MCP-1 levels were increased in the urine of diabetic db/db mice, correlating with the severity of diabetic albuminuria.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalNephron Extra
Volume5
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

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All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Chung, C. H., Fan, J., Lee, E. Y., Kang, J. S., Lee, S. J., Pyagay, P. E., Khoury, C. C., Yeo, T. K., Khayat, M. F., Wang, A., & Chen, S. (2015). Effects of tumor necrosis factor-α on podocyte expression of monocyte chemoattractant protein-1 and in diabetic nephropathy. Nephron Extra, 5(1), 1-18. https://doi.org/10.1159/000369576