Extracellular microenvironment and cytokine profile of the ureterovesical junction in children with vesicoureteral reflux.
OBJECTIVE
Vesicoureteral reflux is caused by a defective valve mechanism of the ureterovesical junction. Previous studies have revealed structural and metabolic changes in the intravesical ureter, impairing its contractile properties. Smooth musculature and nerves are replaced by collagen, while matrix degrading enzymes are over expressed. We investigated the presence of regulating cytokines and the extracellular matrix composition to elucidate further the pathophysiology of vesicoureteral reflux.


METHODS
Ureteral endings were obtained from 28 children during antireflux surgery, and 14 age matched autopsy specimens served as controls. Routine histological sections were immunostained for insulin-like growth factor-1, nerve growth factor, transforming growth factor-beta1, tumor necrosis factor-alpha and vascular endothelial growth factor. Smooth muscle staining was supplemented by tenascin C, tetranectin and fibronectin detection. Staining patterns were investigated using computer assisted, high power field magnification analyses.


RESULTS
Tumor necrosis factor-alpha and transforming growth factor-beta1 were significantly more abundant in vesicoureteral reflux samples, whereas insulin-like growth factor-1, nerve growth factor and vascular endothelial growth factor were more prevalent in healthy controls. Fibronectin was intensely expressed in refluxing ureters, while it was scarce in healthy children. Tenascin C was notable within the urothelium of both groups. Only vesicoureteral reflux samples displayed tenascin C in the musculature and connective tissue. Tetranectin staining was only detected in vesicoureteral reflux.


CONCLUSIONS
Several cytokines are differentially expressed in primary refluxing ureters, indicating an ongoing tissue remodeling process in the ureterovesical junction region. Additionally, the smooth muscle coat is widely lacking, while extracellular matrix proteins typical for tissue shrinkage and reorganization are over expressed. These alterations are likely to contribute to the malfunctioning active ureteral valve mechanism in primary vesicoureteral reflux.
Department of Pediatric Urology, Medical University Innsbruck, Innsbruck, Austria. christian.radmayr@i-med.ac.at
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Schwentner
J
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Oswald
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Lunacek
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AE
Pelzer
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H
Fritsch
B
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Schlenck
A
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Karatzas
G
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Bartsch
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Radmayr
D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D005110:Extracellular Space; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007365:Intercellular Junctions / Q000473:pathology; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000473:pathology*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013002:Somatomedins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018666:Ureteroscopy; D019459:Urothelium / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014718:Vesico-Ureteral Reflux / Q000378:metabolism* / Q000473:pathology*
D015415:Biomarkers; D016207:Cytokines; D013002:Somatomedins; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A