Increased expression of TGF-beta1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas.
BACKGROUND
Hemodialysis fistula dysfunction due to stenotic lesions remains a frequent cause of hospitalization for hemodialysis patients. Transforming growth factor-beta(TGF-beta) and insulin-like growth factor-I (IGF-I) are known to be involved in atherogenesis. The latent TGF-beta1 binding protein-1 (LTBP-1) targets extracellular matrix (ECM) interactions and is involved in the regulation of TGF-beta latency.


METHODS
We investigated the expression of TGF-beta1, LTBP-1 and IGF-I in 15 occluded or severely narrowed vein segments of primary arteriovenous fistulas, in 29 non-stenosed control veins from uremic, pre-dialysis patients, and in 15 non-stenosed control saphenous veins obtained from patients undergoing aortocoronary bypass grafting. Immunohistochemistry was performed on snap-frozen tissue specimens using antibodies recognizing either the latency-associated peptide of TGF-beta1 (96-1), LTBP-1 (Ab39) or IGF-I. Serum levels of TGF-beta1 and IGF-I were determined by commercially available IRMA.


RESULTS
In stenosed hemodialysis fistulas, a pronounced intimal thickening with deposition of ECM was observed with light and electron microscopy. Infiltrating cells were seen in stenosed vessels, mostly in areas of intimal hyperplasia and in the media. TGF-beta1, LTBP-1 and IGF-I expression were mostly localized in the neointimal and medial layers, and were significantly higher than in the control groups. A positive correlation between the presence of inflammatory cells and the staining intensity for TGF-beta1, LTBP-1 and IGF-I was found in all vessels analyzed.


CONCLUSIONS
Neointimal thickening of primary arteriovenous fistulas represents a local inflammatory process and appears to be associated with increased protein expression of TGF-beta1 and IGF-I. While local IGF-I is likely to stimulate smooth muscle cell proliferation in this setting, TGF-beta1 may be an important trigger of ECM production and deposition.
Stracke
Sylvia
S
Department of Internal Medicine II, Division of Nephrology, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.
Konner
Klaus
K
Köstlin
Isabella
I
Friedl
Reinhard
R
Jehle
Peter M
PM
Hombach
Vinzenz
V
Keller
Frieder
F
Waltenberger
Johannes
J
D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D002352:Carrier Proteins / Q000378:metabolism; D003251:Constriction, Pathologic / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D012016:Reference Values; D006435:Renal Dialysis; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014511:Uremia / Q000378:metabolism; D014657:Vasculitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D014680:Veins / Q000378:metabolism
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I