Abstract
The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tissue injury to mediate local tissue responses including inflammation and tissue remodeling. We found that in various models of kidney disease, Fn14 expression (mRNA and protein) is upregulated in the kidney. These models include: lupus nephritis mouse models (Nephrotoxic serum Transfer Nephritis and MRL.Faslpr/lpr), acute kidney injury models (Ischemia reperfusion injury and Folic acid injury), and a ZSF-1 diabetic nephropathy rat model. Fn14 expression levels correlate with disease severity as measured by disease histology. We have also shown for the first time the detection of soluble Fn14 (sFn14) in the urine and serum of mice. Importantly, we found the sFn14 levels are markedly increased in the diseased mice and are correlated with disease biomarkers including proteinuria and MCP-1. We have also detected sFn14 in human plasma and urine. Moreover, sFn14 levels, in urine are significantly increased in DN patients and correlated with proteinuria and MCP-1 levels. Thus our data not only confirm the up-regulation of Fn14/TWEAK pathway in kidney diseases, but also suggest a novel mechanism for its regulation by the generation of sFn14. The correlation of sFn14 levels and disease severity suggest that sFn14 may serve as a potential biomarker for both acute and chronic kidney diseases.
Highlights
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, Apo3L, and TNFSF12) is a cytokine that belongs to the TNF superfamily
The nephrotoxic nephritis (NTN) model was induced by immunizing mice with anti-rat glomerular serum diluted in PBS to final concentrations of 8% or 32% (Fig 1)
We found that kidney Fn14 protein and mRNA expression were both significantly increased in MRL/lpr mice at 22 weeks of age when compared to age matched control mice (MRL/MpJ) that do not develop SLE (Fig 1E–1F)
Summary
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, Apo3L, and TNFSF12) is a cytokine that belongs to the TNF superfamily. TWEAK binds and activates fibroblast growth factor-inducible-14 (Fn14, TWEAK receptor, TNFRSF12A, CD266), a TNF receptor superfamily (TNFRSF) protein [1,2,3]. The human TWEAK gene encodes a type II transmembrane glycoprotein of 249 amino acids. Proteolytic processing of membrane TWEAK generates soluble TWEAK (156-amino acids) [13,14,15]. TWEAK is broadly expressed, especially at relatively high levels in monocytes and macrophages. The intracellular domain (29 amino acids) of Fn14 lacks a death domain It contains TNFR-associated factor (TRAF)-binding sites that can initiate the signaling events through recruitment of TRAF2/5 and activation of IKK and MAP kinase pathways [24, 25]. It should be noted that the role of CD163 in regulating TWEAK pathway remains controversial as Fick et al, have reported no evidence for an interaction of CD163 and TWEAK at biologically meaningful concentrations [29]
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