Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. Sep 7, 2018; 7(5): 96-107
Published online Sep 7, 2018. doi: 10.5527/wjn.v7.i5.96
A small molecule fibrokinase inhibitor in a model of fibropolycystic hepatorenal disease
Prani Paka, Brian Huang, Bin Duan, Jing-Song Li, Ping Zhou, Latha Paka, Michael A Yamin, Scott L Friedman, Itzhak D Goldberg, Prakash Narayan
Prani Paka, Brian Huang, Bin Duan, Jing-Song Li, Ping Zhou, Latha Paka, Michael A Yamin, Itzhak D Goldberg, Prakash Narayan, Department of Research and Development, Angion Biomedica Corp., Uniondale, NY 11553, United States
Scott L Friedman, Icahn School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, United States
Author contributions: Narayan P, Paka P, Yamin MA, Paka L and Friedman SL substantially contributed to the conception and design of the study, acquisition, analysis and interpretation of data; Goldberg ID has contributed for funding acquisition and scientific advice; Narayan P drafted the article related to the intellectual content of the manuscript; Paka L made revisions for the reviewer’s comments for the final version of the article to be published; Paka P, Huang B and Zhou P also performed in vitro work; Duan B and Li JS performed animal care, experimental dosing, pre and post-surgical procedures in animal models; all authors reviewed and approved the final version of the article to be published.
Institutional animal care and use committee statement: Angion’s Animal Welfare Assurance # A4532-01. All the study protocols were designed to minimize pain and distress to the animals and were reviewed approved by our Angion’s animal care and use committee.
Conflict-of-interest statement: Dr. Narayan reports in addition, Dr. Narayan has a patent null issued.
Data sharing statement: Angion Biomedica is a for-profit small business engaged in developing therapeutics for unmet medical needs. In keeping with corporate policy, data and research resources generated by the company are proprietary. Once all intellectual property that results from the generation of the data and research resources is protected via filing of patents, data and research resources generated will be made available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Prakash Narayan, PhD, Research Scientist, Department of Research and Development, Angion Biomedica Corp., 51 Charles Lindbergh Blvd., Uniondale, NY 11553, United States. pnarayan@angion.com
Telephone: +1-516-3261200
Received: March 25, 2018
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
Processing time: 167 Days and 10.2 Hours
ARTICLE HIGHLIGHTS
Research background

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.

Research motivation

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.

Research objectives

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.

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

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.