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.
OBJECTIVE
Several lines of evidence suggest that the infiltration of macrophages and the expression of alpha-smooth muscle actin in myofibroblasts play important roles in the pathogenesis of tubulointerstitial fibrosis. 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 documented.


METHODS
We investigated the infiltration of macrophages and the expression of alpha-smooth muscle actin in interstitial fibrosis caused by a unilateral ureteral obstruction (UUO) experimental model.


RESULTS
The result showed that the macrophages were immobilized at the interstitium and alpha-smooth muscle actin was up-regulated in myofibroblasts of both cortex and medulla at day 3 when interstitial volume start to increase significantly. The highest expression of alpha-smooth muscle actin was detected at day 5 and the most intense infiltration 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 immunosuppressive agent, on the interstitial fibrosis induced by UUO, demonstrating that mizoribine, but not prednisolone, significantly improves the tubulointerstitial fibrosis by suppressing the macrophage infiltration and the expression of alpha-smooth muscle actin.


CONCLUSIONS
We discuss the pathological roles of macrophages and alpha-smooth muscle actin in tubulointerstitial fibrosis induced by UUO treatment. We also emphasize the pharmacological basis and clinical relevance of mizoribine in the treatment of interstitial fibrosis caused by obstructive nephropathy.
Sakai
T
T
Second Department of Internal Medicine, Jikei University School of Medicine, Japan.
Kawamura
T
T
Shirasawa
T
T
D000199:Actins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D002465:Cell Movement; D005260:Female; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012263:Ribonucleosides / Q000627:therapeutic use*; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
D000199:Actins; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine