A small molecule fibrokinase inhibitor in a model of fibropolycystic hepatorenal disease
| Autor: | Prakash Narayan, Brian Huang, Scott L. Friedman, Latha Paka, Prani Paka, Jingsong Li, Itzhak D. Goldberg, Michael A. Yamin, Ping Zhou, Bin Duan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Urinary system Urology Renal function Kidney 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Congenital hepatic fibrosis Medicine Autosomal recessive polycystic kidney disease Creatinine biology business.industry Basic Study medicine.disease Fibrosis 030104 developmental biology medicine.anatomical_structure Cyst Cystatin C chemistry Liver 030220 oncology & carcinogenesis biology.protein Albuminuria Therapy medicine.symptom business Hepatic fibrosis |
| Zdroj: | World Journal of Nephrology |
| ISSN: | 2220-6124 |
| Popis: | Aim To evaluate the novel platelet-derived growth factor receptor and vascular endothelial growth factor receptor dual kinase inhibitor ANG3070 in a polycystic kidney disease-congenital hepatic fibrosis model. 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 gelatinase-associated 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 hepato-renal transplantation in patients with fibropolycystic disease. |
| Databáze: | OpenAIRE |
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