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.

Huangkui capsule attenuates renal fibrosis in diabetic nephropathy rats through regulating oxidative stress and p38MAPK/Akt pathways, compared to α-lipoic acid

“…Indeed, the kidney is not a main target organ of insulin, and thus insulin action on p-Akt in the kidney is weak. In addition, it is undeniable that HKC may have the independent antergic effect of TNF-α, an inducer of p-AKT (Chung et al, 2015), moreover, the reduction of TNF-α may also be the potential mechanism of HKC for the protection of the kidney. All in all, regarding these interesting issues, we could not draw a clear conclusion in vivo.…”

RETRACTED ARTICLE: TN-2 modulates LPS-induced inflammatory response in human renal tubular epithelial cells by blocking TLR4-mediated NF-κB activation via MyD88- and TRIF-dependent mechanism

“…Recent studies have shown that the activation of various inflammatory molecules, such as cytokines (IL-6, IL-8, IL-1b, and TNF-a) [24], adhesion molecules (ICAM-1) [25], chemokines (MCP-1) [26], synthetase (iNOS and COX-2), and growth factors (VEGF, TGF-b) [27] contribute to the progression of DN. In our study, LPS up-regulated the production of a spectrum of inflammatory molecules in hRPTECs, including IL-6, IL-8, IL-1b, TNF-a, iNOS, COX-2, MCP-1 and ICAM-1.…”

Transforming growth factor-β1/Smad3-independent epithelial–mesenchymal transition in type I collagen glomerulopathy

“…This may be, in part, due to TGF-β1/Smad3-induced ECM production occurring by way of Smad3 binding to the COL1A2 promoter, which, while functional in Col1a2-deficient mice, may not increase homotrimeric type I collagen production. Col1a2-deficient/Smad3-deficient 16,53 and Smad-3-independent TGF-β1 signaling (such as Ras/Raf, extracellular signal-regulated kinase-mitogen-activated protein kinase, and nuclear factor κB) remain to be investigated. 46,52 TNF-α has been shown to be released by mesangial cells upon exposure to certain pathogens.…”