Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model
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ORIGINAL PAPER
Roxadustat (FG‑4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model Victoria H. Ko1,2 · Lumeng J. Yu1,2 · Duy T. Dao1,2 · Xiaoran Li1,2 · Jordan D. Secor1,2 · Lorenzo Anez‑Bustillos1,2 · Bennet S. Cho1,2 · Amy Pan1,2 · Paul D. Mitchell3 · Hiroko Kishikawa1,2 · Mark Puder1,2 Received: 18 February 2020 / Accepted: 6 July 2020 © Springer Nature B.V. 2020
Abstract Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously. Keywords Vascular endothelial growth factor · Pigment epithelium-derived factor · Compensatory lung growth · Pneumonectomy · Roxadustat · Vadadustat Abbreviations CKD Chronic kidney disease CLG Compensatory lung growth DMSO Dimethyl sulfoxide H&E Hematoxylin and eosin HIF Hypoxia inducible factor IPF Idiopathic pulmonary fibrosis PBS Phosphate-buffered saline PBST Phosphate-buffered saline with 0.5% Triton-X
PEDF Pigment-epithelial derived factor PHD Prolyl hydroxylase POD Post-operative day P-VEGFR2 Phosphorylated-vascular endothelial growth factor receptor 2 TBST Tris-buffered saline and Tween 20 TLC Total lung capacity VEGF Vascular endothelial growth factor VEGFR2 Vascular endothelial growth factor receptor 2
* Mark Puder [email protected]
Introduction
1
Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2
Department of Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA 02115, USA
3
Institutional Centers for Clinical and Translational Research, Boston Child
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