A Rho-kinase inhibitor, fasudil, attenuates progressive glomerulosclerosis induced by daunorubicin in rats.
Accumulating evidence suggests that the small G protein Rho and its downstream effector Rho kinase may play important roles in kidney biology. The present study examined the effects of a Rho-kinase inhibitor, fasudil, on daunorubicin-induced progressive glomerulosclerosis and explored the underlying mechanism by which fasudil ameliorates glomerulosclerosis. Thirty-six male SD rats were randomly allocated into sham-operation group (sham group, n=12), unilateral nephrectomy (UNX)+daunorubicin (DRB) group (model group, n=12), UNX+DRB+Fasudil group (treatment group, n=12). Two to four weeks after the establishment of the animal model, 6 rats in each group were taken randomly for the detection of 24-h urine protein excretion. Kidney sections were examined by HE and PAS staining, immunohistochemistry and transmission electric microscopy (TEM). The expression of Rho-kinase mRNA and P27 mRNA in kidney were detected by RT-PCR. It was found that the 24-h urine protein excretion in model group was increased significantly as compared with sham group (P<0.01). But this increase was significantly suppressed by fasudil (P<0.05). At 4 week, the foot process effacement in podocytes, mesangial proliferation and ECM accumulation were observed in model group, presenting as focal segmental glomerulosclerosis. But in the treatment group, the fasudil alleviated glomerular injury, with proliferating cell nuclear antigen (PCNA)-positive cell infiltration ameliorated and the expression of P27 increased. The expression of Rho-kinase mRNA was significantly enhanced in model group and was suppressed in treatment group. Moreover, fasudil up-regulated the mRNA expression of P27. Our study demonstrated that the glomerulosclerosis was substantially ameliorated by inhibiting the expression of Rho-kinase. It is suggested that Rho-kinase pathway is involved in the renal injury and the inhibition of Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury.
Deng
Bingqing
B
Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. deng.bingqing@gmail.com
Yang
Xiao
X
Zhu
Zhonghua
Z
Zhang
Chun
C
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003630:Daunorubicin; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil; D003630:Daunorubicin