A small molecule fibrokinase inhibitor in a model of fibropolycystic hepatorenal disease

• 作者: Bin Duan Brian Huang Itzhak D Goldberg Jing-Song Li Latha Paka Michael A Yamin Ping Zhou Prakash Narayan Prani Paka Scott L Friedman
• 来源期刊: 世界肾病学杂志：英文版
• 学科: 医学
• 关键词: Congenital hepatic FIBROSIS CYST FIBROSIS Autosomal RECESSIVE POLYCYSTIC KIDNEY disease KIDNEY Liver Therapy
• 年，卷（期）: 2018,（5）
• 页码范围: 96-107
• 页数: 12页
• 分类号: R

摘要

AIM To evaluate the novel platelet-derived growth factor receptor and vascular endothelial growth factor receptor dual kinase inhibitor ANG3070 in a polycystic kidney METHODS At 6 wk of age,PCK rats were randomized to vehicle or ANG3070 for 4 wk.At 10 wk,24 h urine and left kidneys were collected and rats were continued on treatment for 4 wk.At 14 wk,24 h urine was collected,rats were sacrificed,and liver and right kidneys were collected for histological evaluation.For Western blot studies,PCK rats were treated with vehicle or ANG3070 for 7 d and sacrificed approximately 30 min after the last treatments.RESULTS Compared to the wild-type cohort,the PCK kidney(Vehicle cohort)exhibited a marked increase in kidney and liver mass,hepato-renal cystic volume,hepato-renal fibrosis and hepato-renal injury biomarkers.Intervention with ANG3070 in PCK rats decreased kidney weight,reduced renal cystic volume and reduced total kidney hydroxyproline,indicating significantly reduced rental interstitial fibrosis compared to the PCK-Vehicle cohort.ANG3070 treatment also mitigated several markers of kidney injury,including urinary neutrophil gelatinaseassociated lipocalin,kidney injury molecule-1,cystatin C and interleukin-18 levels.In addition,this treatment attenuated key indices of renal dysfunction,including proteinuria,albuminuria and serum blood urea nitrogen and creatinine,and significantly improved renal function compared to the PCK-Vehicle cohort.ANG3070 treatment also significantly decreased liver enlargement,hepatic lesions,and liver fibrosis,and mitigated liver dysfunction compared to the PCK-Vehicle cohort.CONCLUSION These results suggest that ANG3070 has the potential to slow disease,and may serve as a bridge toward hepatorenal transplantation in patients with fibropolycystic disease.