Role Of Osteopontin And Nuclear Transcription Factor In Renal Tissues Of Rats With Chronic Cyclosporine A Nephrotoxicity

Objective:This study was designed to To investigate the role of osteopontin (OPN) and nuclear transcription factor in a rat model of chronic cyclosporine A (CsA) nephrotoxicity.Methods:Male Sprague-Dawley rats maintained on a low salt diet were treated daily with vehicle (olive oil,1ml/kg/d, s.c.) and CsA (15mg/kg s.c.) for4weeks. Renal histopathology was estimated by trichrome staining (tubulointerstitial fibrosis) and immunohistochemistry (ED-1). In addition, OPN mRNA and protein expression and nuclear transcription factor (NF-κB and AP-1) were studied by northern blot, immunohistochemistry, EMSA, and immunoblotting.Results:Compared with VH-treated rats, CsA-treated rats displayed striped tubulointerstitial fibrosis (38.9±3.3%/mm2vs.0.0±0.0%/mm2, P<0.01) and increased ED-1-positive cells (89±9vs.7±2, P<0.01). Compared with VH-treated rats, CsA-treated rats showed significant upregulation of OPN mRNA and protein expression in proximal tubular cells, which mainly localized to areas of severe injured tissues. Correlation analysis revealed that upregulation of OPN mRNA expression was correlated with tubulointerstitial fibrosis (r=0.959, P<0.01) and stimulation of NF-κB and AP-1activity (NF-κB:r=0.773,P<0.01; AP-1:r=0.619, P=0.01, respectively).Conclusion:These findings suggest that upregulation of OPN by CsA is closely associated with the severity of tubulointerstitial fibrosis, and that this may be through activating NF-κB and AP-1in chronic CsA nephrotoxicity.