Loss of interstitial cells of Cajal and gap junction protein connexin 43 at the vesicoureteral junction in children with vesicoureteral reflux.
OBJECTIVE
Symmetrical muscular contractions and unidirectional peristalsis are prerequisites for competent valve function at the ureterovesical junction. Interstitial cells of Cajal (ICCs) are pacemaker cells that create and coordinate peristaltic motility. We investigated ureteral endings immunohistochemically to elucidate the presence of c-kit positive ICCs as well as the occurrence of gap junction protein connexin 43 in children with vesicoureteral reflux (VUR) to identify a possible pathogenic factor of an insufficient antireflux mechanism.


METHODS
Distal ureteral specimens were obtained from 27 children undergoing antireflux surgery. Routine histological paraffin embedded sections were immunostained detecting the c-kit proto-oncogene to study the presence of ICCs as well as connexin 43 positive cells to determine the gap junction density within the ureteral wall. Age matched nonrefluxing ureteral endings served as controls. All investigations were done using high power field magnification for semiquantitative analysis and statistically analyzed.


RESULTS
ICCs were present in refluxing and nonrefluxing ureteral endings. Healthy individuals displayed significantly more ICCs than children with VUR. Connexin 43 immunoreactivity was significantly decreased in all refluxing ureteral specimens, whereas it was homogeneously distributed in normal controls.


CONCLUSIONS
C-kit positive ICCs are found at the ureterovesical junction. Refluxing ureteral endings significantly lack these pacemaker cells, implying a malfunctioning valve mechanism permitting VUR. A substantial decrease in gap junctions in this region adversely affects intercellular signaling, aggravating coordinated peristalsis, which is essential for a competent anti-reflux mechanism.
Schwentner
Christian
C
Department of Pediatric Urology, Institute of Anatomy, Medical University Innsbruck, Innsbruck, Austria.
Oswald
Josef
J
Lunacek
Andreas
A
Fritsch
Helga
H
Deibl
Martina
M
Bartsch
Georg
G
Radmayr
Christian
C
D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D011336:Probability; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis*; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D016896:Treatment Outcome; D018666:Ureteroscopy / Q000379:methods; D013520:Urologic Surgical Procedures / Q000379:methods; D014718:Vesico-Ureteral Reflux / Q000473:pathology* / Q000503:physiopathology* / Q000601:surgery
D015415:Biomarkers; D018031:Connexin 43; D017630:Connexins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit