Insulin-like growth factor-1 expression in reflux nephropathy.
BACKGROUND
Reflux nephropathy (RN) is recognised as a major cause of end-stage renal failure in children and young adults. Insulin-like growth factor-1 (IGF-1), a peptide growth factor produced by collecting ducts, and its receptor, insulin-like growth factor-1 receptor (IGF-1R), are present in the glomeruli and basolateral membrane of renal proximal tubular cells. Exogenous IGF-1 has been shown to enhance proliferation and reduce apoptosis of tubular cells following renal injury.


METHODS
We designed this study to investigate the expression of IGF-1 in RN. The kidney specimens from 15 children with RN were obtained at the time of nephrectomy. Control material included normal kidney specimens obtained from adult patients during partial nephrectomy for an incidentaloma. Single-label immunofluorescence histochemistry was carried out using polyclonal antibodies to IGF-1 and IGF-1R employing laser scanning confocal microscopy. Double-label immunofluorescence histochemistry was carried out using monoclonal antibodies to vimentin and clusterin to assess tubulointerstitial fibrosis. IGF-1 and IGF-1R gene expression were evaluated by in situ hybridisation (ISH). The TUNEL method was utilised to assess tubular apoptosis.


RESULTS
In the normal kidney there was strong IGF-1 and IGF-1R immunoreactivity in the proximal tubules, whereas IGF-1 and IGF-1R immunoreactivity was markedly reduced in RN specimens. Strong IGF-1 and IGF-1R mRNA expression was observed in the proximal tubules in normal kidneys, whereas IGF-1 and IGF-1R mRNA expression was undetectable in RN. Renal tubulointerstitial expression of vimentin and clusterin was markedly increased in RN kidneys. Decreased IGF-1 and IGF-1R expression in RN strongly correlated with severity of tubular apoptosis in RN compared with controls.


CONCLUSIONS
These data suggest that the downregulation of IGF-1 and IGF-1R may play an important role in the pathogenesis of RN, at least in part by increasing interstitial collagen deposition and tubular apoptosis.
Chertin
Boris
B
Children's Research Centre, Our Lady's Hospital for Sick Children, University College Dublin, Dublin, Ireland.
Farkas
Amicur
A
Puri
Prem
P
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D051152:Clusterin; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000601:surgery; D018832:Molecular Chaperones / Q000096:biosynthesis; D009392:Nephrectomy; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D014718:Vesico-Ureteral Reflux / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D014746:Vimentin / Q000096:biosynthesis
C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D014746:Vimentin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1