Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model

Angiogenesis. 2020 Nov;23(4):637-649. doi: 10.1007/s10456-020-09735-9. Epub 2020 Jul 14.

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: Compensatory lung growth; Pigment epithelium-derived factor; Pneumonectomy; Roxadustat; Vadadustat; Vascular endothelial growth factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Compliance
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Eye Proteins
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Isoquinolines / administration & dosage
  • Isoquinolines / pharmacology*
  • Lung / drug effects
  • Lung / growth & development*
  • Lung / physiology*
  • Lung / surgery
  • Male
  • Mice, Inbred C57BL
  • Models, Biological*
  • Nerve Growth Factors
  • Organ Size / drug effects
  • Phosphorylation / drug effects
  • Physical Conditioning, Animal
  • Picolinic Acids
  • Pneumonectomy
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / growth & development
  • Respiratory Function Tests
  • Serpins
  • Total Lung Capacity
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Eye Proteins
  • FG-4592
  • Isoquinolines
  • Nerve Growth Factors
  • Picolinic Acids
  • Serpins
  • Vascular Endothelial Growth Factor A
  • pigment epithelium-derived factor
  • vadadustat
  • Vascular Endothelial Growth Factor Receptor-2
  • Glycine