Dataset Information

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.

SUBMITTER: Sharif MN

PROVIDER: S-EPMC4865213 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease.

Sharif M Nusrat MN Campanholle Gabriela G Nagiec Eva E EE Wang Ju J Syed Jameel J O'Neil Shawn P SP Zhan Yutian Y Brenneman Karrie K Homer Bruce B Neubert Hendrik H Karim Riyez R Pullen Nick N Evans Steven M SM Fleming Margaret M Chockalingam Priya P Lin Lih-Ling LL

PloS one 20160512 5

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 ac ...[more]

PMID: 27171494

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Project description:BackgroundSoluble Klotho has multiple systemic salutary effects. In animals, both acute and chronic kidney disease models display systemic Klotho deficiency. As such, there is considerable interest in investigating soluble Klotho as a biomarker in patients with different types and severity of kidney diseases. Unfortunately, there remains uncertainty regarding the best method to measure soluble Klotho in human serum samples.MethodsUsing human serum samples obtained from several clinical cohorts with a wide range of kidney function, we measured soluble Klotho using a commercial enzyme-linked immunosorbent assay (ELISA) as well as with an immunoprecipitation-immunoblot (IP-IB) assay utilizing a synthetic antibody with high affinity and specificity for Klotho. Recovery of spiking with a known amount of exogenous Klotho was tested. A subset of samples was analyzed with and without the addition of a protease inhibitor cocktail at the time of collection or after the first freeze-thaw cycle to determine if these maneuvers influenced performance.ResultsThe IP-IB assay was superior to the ELISA at recovery of exogenous Klotho (81-115% versus 60-81%) across the spectrum of kidney function. Klotho measurements by IP-IB were highly correlated with estimated glomerular filtration rate (eGFR) (R = 0.80, P < 0.001) in comparison with the commercial ELISA, which exhibited minimal correlation with eGFR (R = 0.18, P = 0.12). Use of a protease inhibitor cocktail neither improved nor impaired performance of the IP-IB assay; however, subsequent freeze-thaw cycle resulted in a significant reduction in Klotho recovery and dissipated the correlation between Klotho levels and eGFR. With the ELISA, the use of protease inhibitor cocktail resulted in an increase in intrasubject variability.ConclusionsThe IP-IB assay is preferable to the commercial ELISA to measure soluble Klotho concentrations in never-thawed serum samples of humans with varying severity of kidney disease. However, due to the labor-intensive nature of the IP-IB assay, further research is needed to secure an assay suitable for high-throughput work.

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Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease.

Publications

Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease.

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