Endothelin-Mediated Oncofetal Fibronectin Expression in Chronic Allograft Nephropathy

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Abstract

Background.

Chronic allograft nephropathy is a sclerotic process characterized by an increased extracellular matrix (ECM) protein deposition. Fibronectin (FN) is a major component of ECM. FN has been reported to undergo alternative splicing and produce several isoforms including the extra domain-B (ED-B) containing embryonic isoform. In the present study, we investigated ED-B+ FN expression in chronic allograft nephropathy and its relationship with endothelins (ET).

Methods.

To establish chronic allograft nephropathy, allografts were performed between Fisher 344 → Lewis rats. Allograft recipients were then randomly divided into two groups, allografts and allografts treated with ET receptor antagonist bosentan. Lewis → Lewis recipients were used as isograft controls. Grafts were harvested at 30, 90 and 140 days for histological and gene expression analyses with respect to ED-B+ FN, ET-1 and transforming growth factor-β1 (TGF-β1) mRNA. ED-B+ FN protein levels were assessed by immunohistochemical analysis. Additionally, we analyzed human renal allograft biopsies.

Results.

Our data demonstrates that rat chronic allograft nephropathy is associated with progressive upregulation of ED-B+ FN mRNA and protein. ET-1 and TGF-β1 mRNA were also upregulated. Treatment of allograft recipient rats with bosentan prevented upregulation of ED-B+ FN and TGF-β1. We further show that total FN, ED-B+ FN, ET-1 and TGF-β1 mRNA expression were upregulated in human chronic allograft nephropathy specimens.

Conclusion.

Results obtained from both human and rat renal allograft tissues suggest that expression of ED-B+ FN is upregulated in chronic allograft nephropathy and such upregulation is mediated via ET-1 and its interaction with TGF-β1.

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