Ultrastructural Changes and Expression of Transforming Growth Factor-beta1 in Tacrolimus- Induced Nephropathy / 대한이식학회지

ABSTRACT

PURPOSE: Tacrolimus (FK506) is a new potent immunosuppressive agent which has been used as a primary immunosuppressive agent and rescue therapy for refractory rejection in kidney transplantation. In vitro, on a molecular basis, tacrolimus is 10 to 100 times more potent than cyclosporine. Complications associated with tacrolimus are similar to those seen in cyclosporine, including nephrotoxicity. An early marker of tacrolimus-induced nephropathy is tubular vacuolization, whereas long-term administration of tacrolimus is associated with striped interstitial fibrosis and arteriolar hyalinosis. However, morphological changes and pathogenesis of fibrosis in chronic tacrolimus-induced nephropathy remain poorly understood. Transforming growth factor (TGF)-beta1 has been implicated in the fibrosis of a number of chronic diseases of the kidney and other organs. This study was designed to clarify the ultrastructural changes of tacrolimus-induced nephropathy, and to evaluate the relationship between tacrolimus- induced nephropathy and expression of TGF-beta1. METHODS: Male ICR mice received tacrolimus daily at a dose of 2.5 mg/kg by intraperitoneal route for 12 weeks and sacrified 1, 4, 8, 10, and 12 weeks after the initiation of the study, respectively. The kidneys were removed, the cortex is carefully dissected from the medulla, and the tissues are processed for evaluation by light microscopy, electron microscopy, immunohistochemistry and RT-PCR for RNA analysis. RESULTS: Characteristic histological changes of tacrolimus-induced nephropathy were peritubular capillary and intraglomerular capillary congestions, vacuolizations of the tubular epithelium, pericapillary focal fibrosis, and tubular atrophy. Tacrolimus- treated kidneys had a progressive increase in the expression of TGF-beta1, especially in the glomerular and interstitial capillary endothelial cells and atrophied tubular epithelial cells. TGF-beta1 mRNA is expressed persistently in tacrolimus- treated mice for 12 weeks. CONCLUSION: It can be concluded that TGF-beta1 may be involved in the fibrogenesis in the tacrolimus-induced nephropathy.