Extracellular microenvironment and cytokine profile of the vesicoureteral junction in children with vesicoureteral reflux

PURPOSE

Vesicoureteral reflux (VUR) is caused by a defective valve mechanism of the ureterovesical junction (UVJ). Previous studies revealed structural and metabolic changes in the distal ureter impairing its contractile properties. Ureteral musculature and nerves are replaced by interstitial collagen while matrix degrading enzymes are overexpressed. We investigated the expression pattern of regulating cytokines and the extracellular matrix composition to elucidate those changes.

MATERIAL AND METHODS

Ureteral endings were obtained from 29 children (mean 48 months) during reimplantation. Ureters from age-matched autopsies served as control, and α, TGF-α Histological sections were immunostained detecting IGF, NGF, TNF- VEGF; smooth muscle staining was done to assess general morphology supplemented by Tenascin C-, Tetranectin-, and Fibronectin-detection. Expression patterns were investigated using semi-quantitative computer-assisted high power field magnification analyses.

RESULTS

α and TGF-α Smooth muscle architecture was defective in VUR. TNF- was abundant in VUR-samples (14.96 vs. 3.45 and 105.64 vs. 55.6 cells per HPF; p<0.0001) whereas IGF, NGF and VEGF were more prevalent in healthy controls (145.71 vs. 32.66, 89.54 vs. 41.23 and 165.43 vs. 69.74 cells per HPF; p<0.0001). Fibronectin was strongly expressed in refluxing ureters - mainly cell-bound - while it was scarce in healthy children. Tenascin-C was notable within the smooth musculature and urothelium of both groups (cytoplasma in controls and inside the nucleus in refluxers). Tetranectin-staining was only detected in cases of VUR.

CONCLUSIONS

A broad variety of cytokines are differentially expressed in refluxing ureters indicating an ongoing tissue remodelling process in the UVJ-region. Additionally, the smooth muscle coat is widely lacking while extracellular matrix proteins being typical for tissue shrinkage and dysplasia are overexpressed. Those alterations are likely to contribute to the malfunctioning valve mechanism in primary VUR.

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