Co-Authors:
Benchetrit, S., Department of Nephrology and Hypertension, Sapir Medical Center, Kfar Saba 44281, Israel
Yarkoni, S., Collgard Biopharmaceuticals Ltd., Tel Aviv, Israel
Rathaus, M., Department of Nephrology and Hypertension, Sapir Medical Center, Kfar Saba 44281, Israel
Pines, M., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Beit Dagan, Israel
Rashid, G., Department of Nephrology and Hypertension, Sapir Medical Center, Kfar Saba 44281, Israel
Bernheim, J., Department of Pathology, Sapir Medical Center, Kfar Saba 44281, Israel, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
Bernheim, J., Department of Nephrology and Hypertension, Sapir Medical Center, Kfar Saba 44281, Israel
Abstract:
Background: Halofuginone is a novel antifibrotic agent that can reverse the fibrotic process by specific inhibition of collagen type I synthesis. Objectives: To evaluate the effect of Halo on the development of glomerulosclerosis and interstitial fibrosis in the 5/6 nephrectomy rat model. Methods: Male Wistar rats were assigned to undergo 5/6 NX or sham operation, and then divided into three groups: 5/6 NX rats (NX-Halo and NX-Control) and sham. Systolic blood pressure, proteinuria and body weight were determined every 2 weeks. At sacrifice (10 weeks) creatinine clearance was evaluated and remnant kidneys removed for histologic examination, sirius red staining and in situ hybridization. Results: Systolic blood pressure increased progressively in both 5/6 NX groups. Halo slowed the increase in proteinuria in 5/6 NX rats. As expected, creatinine clearance was lower in 5/6 NX groups when compared to sham rats. Creatinine clearance was significantly higher in the NX-Halo group at the end of the study period. Histologic examination by light microscopy showed significanty less severe interstitial fibrosis and glomerulosclerosis in Halo-treated rats. The increase in Collagen α1 (I) gene expression and collagen staining after nephrectomy was almost completely abolished by Halo. Conclusions: Halofuginone reduced proteinuria as well as the severity of interstitial fibrosis and glomerulosclerosis in 5/6 NX rats. The renal beneficial effect of Halo was also demonstrated by the blunted decrease in creatinine clearance observed in the treated animals.