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
In autosomal recessive polycystic kidney disease (ARPKD)-congenital hepatic fibrosis (CHF), a genetically acquired and congenital disease, mutations in the human PKHD1 gene or mutations in PKHD1 orthologs in rats and mice are required for the development of ARPKD-CHF. Nevertheless, experimental studies have identified that epithelial cells drive changes in the renal interstitium, with alterations made to the cystic epithelia followed by changes in the interstitial fibroblasts and progressive accumulation of extracellular matrix. This leads to the development of renal fibrosis within the kidney and/or liver. For children, nephrectomy and dialysis or kidney or 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 (PDGF) and vascular endothelial growth factor (VEGF) are the intermediaries between the cystic and fibrotic components of progressive fibropolycystic disease, and that a PDGFR + VEGFR dual inhibitor can be a novel therapeutic approach.
The development of new therapies that prevent the transition from cystogenesis to fibrosis or adenocarcinoma in advanced stages of ARPKD-CHF will have tremendous clinical potential and decrease the number of hepato-renal transplants in patients with ARPKD-CHF.
The main objectives of our studies were to evaluate a novel PDGFR and VEGFR dual kinase inhibitor, ANG3070, in a PKD-CHF model. These studies could lead to a novel therapeutic approach for fibropolycystic kidney disease.
Renal pathology was confirmed in PCK rats at 6 wk compared to the age and gender-matched wild type SD rats. At 6 wk of age, PCK rats were then randomized to vehicle or ANG3070 for 4 wk. At 10 wk, 24 h urine and left kidneys were collected and rats were continued on treatments 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.
A well-characterized PCK rat model was used to study fibropolycystic kidney disease. 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, thus 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. This treatment also significantly attenuated key indices of renal dysfunction, including proteinuria, albuminuria and serum blood urea nitrogen and creatinine, and improved renal function compared to the PCK-Vehicle cohort. ANG3070 treatment also significantly decreased liver enlargement, hepatic lesions, decreased liver fibrosis and mitigated liver dysfunction compared to the PCK-Vehicle cohort. A dose-response study of ANG3070 needs to be evaluated to establish a minimum dose for maximal therapeutic efficacy in this PCK rat model.
The development of new therapies that prevent the transition from cystogenesis to fibrosis or adenocarcinoma in advanced stages of ARPKD-CHF will have tremendous clinical potential. Studies indicate that PDGF and VEGF are the intermediaries between the cystic and fibrotic components of progressive fibropolycystic disease. We have identified and synthesized a novel small molecule PDGFR + VEGFR/KDR dual kinase inhibitor, ANG3070, using molecular modeling coupled with rational drug design, medicinal chemistry and structure activity relationship. We have evaluated ANG3070 therapeutic effects in a rat model of ARPKD-CHF and have proven it to be efficacious in mitigating kidney and liver injury biomarkers and decreasing hepatic and renal dysfunction. These studies could lead to the identification of a novel therapeutic approach in slowing fibropolycystic disease and decreasing the number of hepato-renal transplants in patients with ARPKD-CHF. These results suggest that ANG3070 has the potential in slowing disease, and may serve as a bridge toward hepato-renal transplantation in patients with fibropolycystic disease.
The results of our studies suggest that ANG3070 has the potential therapeutic effect of slowing disease, and may serve as a bridge toward hepato-renal transplantation in patients with the fibropolycystic disease ARPKD-CHF.