Halofuginone reduces the occurrence of renal fibrosis in 5/6 nephrectomized rats

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.