Endothelin-mediated oncofetal fibronectin expression in chronic allograft nephropathy.
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-beta1 (TGF-beta1) 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-beta1 mRNA were also upregulated. Treatment of allograft recipient rats with bosentan prevented upregulation of ED-B FN and TGF-beta1. We further show that total FN, ED-B FN, ET-1 and TGF-beta1 mRNA expression were upregulated in human chronic allograft nephropathy specimens.


CONCLUSIONS
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-beta1.
Siddiqui
Iram
I
Department of Pathology, University of Western Ontario, London, Canada.
Khan
Zia A
ZA
Lian
Dameng
D
Jiang
Jifu
J
Zhong
Robert
R
Garcia
Bertha
B
Chakrabarti
Subrata
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001706:Biopsy; D002648:Child; D002908:Chronic Disease; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006084:Graft Rejection; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009393:Nephritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics; D014184:Transplantation, Homologous
D019332:Endothelin-1; D005353:Fibronectins; D020033:Protein Isoforms; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C121542:oncofetal fibronectin