MIZORIBINE IMPROVES RENAL TUBULOINTERSTITIAL FIBROSIS IN UNILATERAL URETERAL OBSTRUCTION (UUO)-TREATED RAT BY INHIBITING THE INFILTRATION OF MACROPHAGES AND THE EXPRESSION OF ALPHA-SMOOTH MUSCLE ACTIN

Purpose: Several lines of evidence suggest that the infiltration of ma crophages and the expression of alpha-smooth muscle actin in myofibrob lasts play important roles in the pathogenesis of tubulointerstitial f ibrosis. However, the temporal sequence of these pathological changes or the dynamics in the expression of this cytoskeletal molecule in the process of tubulointerstitial fibrosis have not been precisely docume nted. Materials and Methods: We investigated the infiltration of macro phages and the expression of alpha-smooth muscle actin in interstitial fibrosis caused by a unilateral ureteral obstruction (UUO) experiment al model. Results: The result showed that the macrophages were immobil ized at the interstitium and alpha-smooth muscle actin was up-regulate d in myofibroblasts of both cortex and medulla at day 3 when interstit ial volume start to increase significantly. The highest expression of alpha-smooth muscle actin was detected at day 5 and the most intense i nfiltration of macrophages was noted at day 14 while the interstitial volume in renal cortex and medulla continued to increase until day 28. Furthermore, we investigated the effect of mizoribine, an immunosuppr essive agent, on the interstitial fibrosis induced by UUO, demonstrati ng that mizoribine, but not prednisolone, significantly improves the t ubulointerstitial fibrosis by suppressing the macrophage infiltration and the expression of alpha-smooth muscle actin. Conclusions: We discu ss the pathological roles of macrophages and alpha-smooth muscle actin in tubulointerstitial fibrosis induced by UUO treatment. We also emph asize the pharmacological basis and clinical relevance of mizoribine i n the treatment of interstitial fibrosis caused by obstructive nephrop athy.