Epidermal growth factor and monocyte chemotactic peptide-1 expression in reflux nephropathy.
OBJECTIVE
Reflux nephropathy (RN) is recognised as a major cause of end stage renal failure in children and young adults. The histological findings of RN are tubular atrophy and interstitial monocyte infiltration. Epidermal growth factor (EGF) produced by tubular cells playing a pivotal role in the modulation of tubular cell growth, while monocyte chemotactic peptide-1 (MCP-1) is a powerful and specific chemotactic and activating factor for monocytes. It has been suggested that the modulation of local EGF production is directly involved in the pathogenesis of tubular damage. We designed this study to investigate the expression of EGF and MCP-1 in severe reflux nephropathy in order to further understand the pathogenesis of reflux nephropathy.


METHODS
The kidney specimens from 12 children with severe reflux nephropathy were obtained at the time of nephrectomy. Control material included normal kidney specimens obtained from three adult patients during partial nephrectomy for an incidentaloma. Single-label immunofluorescence histochemistry was carried out using polyclonal antibodies to EGF and MCP-1 employing laser scanning confocal microscopy. EGF and MCP-1 gene expression were evaluated by in situ hybridization (ISH). TUNEL method was utilized to assess tubular apoptosis.


RESULTS
In the normal kidney there was strong EGF immunoreactivity in the proximal tubules compared to the reflux nephropathy where there was lack of immunoreactivity in the proximal tubules. Normal kidney demonstrated lack of MCP-1 immunoreactivity, whereas reflux nephropathy kidney showed strong MCP-1 immunoreactivity in the proximal tubules and tubulointerstitial space. In the normal kidney there was marked EGF mRNA expression in the proximal tubules whereas EGF mRNA expression was undetectable in reflux nephropathy kidney. MCP-1 mRNA expression was undetectable in normal kidney, whereas there was strong MCP-1 mRNA expression at the tubulointerstitial level in reflux nephropathy kidney. Decreased EGF expression and increased MCP-1 expression at the tubulointerstitial levels in reflux nephropathy strongly correlated with severity of apoptosis in reflux nephropathy compared with controls.


CONCLUSIONS
Our data suggests that the downregulation of EGF with simultaneous upregulation of MCP-1 may be involved in the pathogenesis of tubulointerstitial damage in reflux nephropathy.
Chertin
Boris
B
Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, University College Dublin, Dublin 12, Ireland.
Farkas
Amicur
A
Puri
Prem
P
D000293:Adolescent; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000032:analysis / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D046508:Culture Techniques; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007223:Infant; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology* / Q000601:surgery; D008297:Male; D009392:Nephrectomy; D011336:Probability; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D015854:Up-Regulation; D014718:Vesico-Ureteral Reflux / Q000150:complications*
D015415:Biomarkers; D018932:Chemokine CCL2; D012333:RNA, Messenger; D004815:Epidermal Growth Factor