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.

Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease

“…Bioanalytical experiments were conducted to generate pivotal model parameters. Since moderate level of sFn14 (22.6 ng/ml) was identified in mouse, 12 plasma sFn14 level in human was measured. The sFn14 was present at significant level in healthy subjects (median level at 1.7 nM).…”

“…The sFn14 levels used in the simulation ranges from the measured level in healthy volunteers to a 10-fold higher level, based on the observations that sFn14 levels are markedly increased in plasma from mouse models of kidney disease compared to healthy mouse. 12 Interestingly, there appears to be a reversed bell-shaped relationship between dose of anti-Fn14 mAb and its Kd. The bell-shape is most pronounced when the mFn14 turnover is slow, i.e., 50 h and is minimal when the mFn14 turnover is rapid, i.e., 0.5 h. Additionally, the dose range due to the 10-fold range in sFn14 levels increases as the mFn14 half-life increases, which is visualized by the band width of the prediction curves.…”

“…This value is similar to the sFn14 concentration range previously reported. 12 In the previous publication, the serum level of sFn14 in 12 healthy individuals was determined to be 2.8 §1.4 nM (14 §7 ng/ml) (mean §SD) using an ELISA assay. 12 Serum turnover rate for sFn14…”

“…Additionally sFn14 was detected in human plasma and urine. 12 Moreover, sFn14 levels in urine are significantly increased in diabetic nephropathy (DN) patients and correlated with proteinuria and MCP-1 levels. 12 Fn14 was originally described as an immediate-early response gene regulated by growth factors in fibroblasts.…”

“…12 Moreover, sFn14 levels in urine are significantly increased in diabetic nephropathy (DN) patients and correlated with proteinuria and MCP-1 levels. 12 Fn14 was originally described as an immediate-early response gene regulated by growth factors in fibroblasts. 13,14 Accumulating evidence has suggested a role for TWEAK activation of Fn14 receptors in the pathogenesis of acute and chronic kidney injury, contributing to both glomerular and tubulointerstitial damage in non-immune and immune-medipt?>ated kidney diseases.…”