title: Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease.
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.
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: M Nusrat
authors.identifier: 0000-0002-2898-9442
authors.initials: MN
authors.lastname: Sharif
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Campanholle
authors.affiliation: Pfizer Worldwide Drug Safety Research and Development, Cambridge, MA, United States America.
authors.forename: Eva E
authors.initials: EE
authors.lastname: Nagiec
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Ju
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pfizer Worldwide Drug Safety Research and Development, Andover, MA, United States of America.
authors.forename: Jameel
authors.initials: J
authors.lastname: Syed
authors.affiliation: Pfizer Worldwide Drug Safety Research and Development, Andover, MA, United States of America.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: O'Neil
authors.affiliation: Pfizer Worldwide Drug Safety Research and Development, Andover, MA, United States of America.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Pfizer Worldwide Drug Safety Research and Development, Andover, MA, United States of America.
authors.forename: Karrie
authors.initials: K
authors.lastname: Brenneman
authors.affiliation: Pfizer Worldwide Drug Safety Research and Development, Andover, MA, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Homer
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Andover, MA, United States of America.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Neubert
authors.affiliation: Global Biological Technology, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Riyez
authors.initials: R
authors.lastname: Karim
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Nick
authors.initials: N
authors.lastname: Pullen
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Margaret
authors.initials: M
authors.lastname: Fleming
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Chockalingam
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, United States of America.
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000473:pathology / Q000652:urine; D000328:Adult; D000818:Animals; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism*; D008181:Lupus Nephritis / Q000097:blood / Q000473:pathology / Q000652:urine; D008297:Male; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000378:metabolism*; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000652:urine; D012995:Solubility; D000074050:TWEAK Receptor; D053719:Tandem Mass Spectrometry; D015854:Up-Regulation
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C000613300:Tnfrsf12a protein, rat; D005492:Folic Acid