Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients.
BACKGROUND
Vascular access failure is the main cause of morbidity in hemodialysis patients. Stenosis of the arteriovenous fistula (AVF) is similar histologically to atherosclerosis. Recent studies showed that interleukin 6 (IL-6) has a key role in the pathogenesis of atherosclerosis by binding 2 specific receptors, gp80 and gp130. When activated, gp130 interacts with a tyrosine kinase, Janus kinase (JAK2), which then activates a transcription factor, signal transducers and activators of transcription (STAT3), directly turning on several proinflammatory genes. The aim of this study is to evaluate gp130 expression and JAK2/STAT3 activation within stenotic AVFs.


METHODS
44 patients undergoing surgery for AVF creation were enrolled; 10 of them had AVF failure with histologically proven AVF stenosis (wall-lumen ratio > 1). A venous fragment of the AVFs was collected during creation and revision of the vascular access. gp130 and gp80 expression, as well as JAK/STAT activation, were evaluated by means of confocal microscopy. Peripheral-blood mononuclear cells were isolated at the time of AVF creation and revision.


RESULTS
gp130 protein expression, barely detectable in native AVFs, was strikingly increased within the venous branch of stenotic AVFs. The signaling subunit of the IL-6 receptor broadly colocalized with gp80, the IL-6-binding subunit. gp130-expressing cells were mainly CD34(+), suggesting that this receptor is expressed primarily by neovasculature endothelial cells. At the same time, a significant increase in phosphorylation of JAK2/STAT3 was observed in endothelial cells of stenotic AVFs. Interestingly, peripheral-blood mononuclear cells isolated at the time of AVF failure presented strikingly greater IL-6 expression compared with dialysis age-matched controls.


CONCLUSIONS
IL-6 receptor activation may have a role in the pathogenesis of AVF failure in hemodialysis patients and may represent a potential therapeutic target in this setting.
Marrone
Daniela
D
Department of Emergency and Transplantation, Division of Nephrology, Dialysis and Transplantation, University of Bari, Italy.
Pertosa
Giovanni
G
Simone
Simona
S
Loverre
Antonella
A
Capobianco
Carmen
C
Cifarelli
Mario
M
Memoli
Bruno
B
Schena
Francesco P
FP
Grandaliano
Giuseppe
G
D000328:Adult; D000368:Aged; D001164:Arteriovenous Fistula / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D003251:Constriction, Pathologic; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008875:Middle Aged; D011446:Prospective Studies; D019947:Receptors, Interleukin-6 / Q000378:metabolism / Q000502:physiology; D006435:Renal Dialysis; D015398:Signal Transduction / Q000502:physiology*
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130