Peer-review started: March 25, 2018
First decision: April 10, 2018
Revised: July 11, 2018
Accepted: August 11, 2018
Article in press: August 11, 2018
Published online: September 7, 2018
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.
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.
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.
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.
Core tip: In autosomal recessive polycystic kidney disease (ARPKD)-congenital hepatic fibrosis (CHF), a genetically acquired and congenital disease, approximately 20-30% of affected patients succumb within the first 1-2 mo of life, with pulmonary insufficiency secondary to renal enlargement as the primary cause of death. For children, nephrectomy and dialysis or kidney liver transplant is often warranted by approximately ten years of age. Other than transplantation, there is no cure for ARPKD-CHF. We report that platelet-derived growth factor and vascular endothelial growth factor are the intermediaries between the cystic and fibrotic components of progressive fibropolycystic disease and ANG3070, a novel dual kinase inhibitor therapy that may serve as an interesting bridge toward hepato-renal transplantation in patients with ARPKD-CHF.