Effects of Tumor Necrosis Factor-α on Podocyte Expression of Monocyte Chemoattractant Protein-1 and in Diabetic Nephropathy
- 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.
- All Author(s)
- C. H. Chung
; J. Fan
; E. Y. Lee
; J. S. Kang
; S. J. Lee
; P. E. Pyagay
; C. C. Khoury
; T. K. Yeo
; M. F. Khayat
; A. Wang
; S. Chen
- Issued Date
- 2015
- Type
- Article
- Keyword
- Akt or protein kinase B; Albuminuria; Diabetic rodent model; Nuclear factor-kappaB; Phosphatidylinositol 3-kinase; TNF receptor 2
- Publisher
- Karger
- ISSN
- 1664-5529
- Citation Title
- Nephron extra
- Citation Volume
- 5
- Citation Number
- 1
- Citation Start Page
- 1
- Citation End Page
- 18
- Language(ISO)
- eng
- DOI
- 10.1159/000369576
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/2510
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