Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease
M Nusrat Sharif, Gabriela Campanholle, Eva E Nagiec, Ju Wang, Jameel Syed, Shawn P O'Neil, Yutian Zhan, Karrie Brenneman, Bruce Homer, Hendrik Neubert, Riyez Karim, Nick Pullen, Steven M Evans, Margaret Fleming, Priya Chockalingam, Lih-Ling Lin, M Nusrat Sharif, Gabriela Campanholle, Eva E Nagiec, Ju Wang, Jameel Syed, Shawn P O'Neil, Yutian Zhan, Karrie Brenneman, Bruce Homer, Hendrik Neubert, Riyez Karim, Nick Pullen, Steven M Evans, Margaret Fleming, Priya Chockalingam, Lih-Ling Lin
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.
Conflict of interest statement
Competing Interests: This work was funded, supported, and performed using Pfizer resources. All authors were employed by Pfizer Inc. during the course of this study. There are no products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
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References
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