Elevated erythropoietin receptor and transforming growth factor-beta1 expression in stenotic arteriovenous fistulae used for hemodialysis.
The issue of whether recombinant human erythropoietin (rhEPO) increases thrombosis of arteriovenous (AV) fistulae used for hemodialysis remains unclear. Thrombosis often occurs at stenotic segments of fistulae where there is marked intimal hyperplasia and extracellular matrix accumulation. Increased expression of transforming growth factor-beta1 (TGF-beta1) has been shown to be involved in the development of atherosclerotic lesions by promoting intimal hyperplasia and extracellular matrix accumulation. To clarify the role of rhEPO in the development of stenosis of AV fistulae, this study examined expression of the erythropoietin receptor (EPO-R), TGF-beta1, plasminogen activator inhibitor type 1 (PAI-1), cellular fibronectin containing an extra domain A (EDA+), and TGF-beta1 mRNA, and assessed in situ rhEPO binding in tissue specimens from seven cutaneous veins and eight patent and seven stenosed portions of AV fistulae of patients undergoing dialysis. Prominent intimal hyperplasia was evident in the stenosed segments. Significant elevation in expression of EPO-R and TGF-beta1 was noted in patent AV fistulae compared to the cutaneous veins. Significant enhancement of EPO-R and TGF-beta expression was detected in the stenotic fistulae. Fibronectin EDA+ and PAI-1 expression was increased in intimal hyperplasia compared to patent fistulae and cutaneous veins. Elevated EPO-R expression was further confirmed by in situ binding of biotin-labeled rhEPO in stenosed tissue specimens. It is hypothesized that increased rhEPO binding due to elevated EPO-R expression contributes to the development of AV fistula stenosis caused by intimal hyperplasia and extracellular matrix accumulation in response to increased TGF-beta1 expression in patients receiving hemodialysis.
Ikegaya
Naoki
N
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Yamamoto
Tatsuo
T
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Takeshita
Akihiro
A
Third Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Watanabe
Takuya
T
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Yonemura
Katsuhiko
K
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Miyaji
Takehiko
T
Maruyama Hospital, Hamamatsu, Japan.
Ohishi
Kazuhisa
K
Maruyama Hospital, Hamamatsu, Japan.
Furuhashi
Mitsuyoshi
M
Maruyama Hospital, Hamamatsu, Japan.
Maruyama
Yukitaka
Y
Maruyama Hospital, Hamamatsu, Japan.
Hishida
Akira
A
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D003251:Constriction, Pathologic; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D006435:Renal Dialysis / Q000009:adverse effects* / Q000379:methods; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D016212:Transforming Growth Factor beta