Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Pulmonary fibrosis is a serious problem in patients with scleroderma lung disease (SLD). Better therapies for pulmonary fibrosis are urgently needed. Identification of new therapeutic targets guides the development of innovative therapies for patients with pulmonary fibrosis. Previous research suggested that a protein termed Response Gene to Complement 32 (RGC-32) is involved in kidney fibrosis, but RGC-32 involvement in SLD or other forms of pulmonary fibrosis has not been explored in depth.
Methods: The levels of RGC-32 mRNA and protein in human lung tissues were studied by RNA-Seq, qRT-PCR, and Western blotting. A chronic bleomycin exposure model of pulmonary fibrosis was used to assess the effects of RGC-32 gene deficiency on collagen accumulation in the lungs in vivo. Experiments in primary human lung fibroblast cultures were used to investigate the effect of plasmid-based RGC-32 gene delivery on TGF-β-induced upregulation of collagen mRNA and protein.
Results: The RNA-Seq data suggested and qRT-PCR confirmed a significant decline in the levels of RGC-32 mRNA in the lung tissues of patients with SLD and idiopathic pulmonary fibrosis (IPF) compared with lung tissues from healthy controls. Similarly, RGC-32 protein levels were significantly decreased in SLD and IPF lung tissues based on western blotting analyses. These observations contrasted previous reports about RGC-32 involvement in several non-fibrotic diseases as well as in kidney fibrosis, all of which implicated elevated levels of RGC-32 in disease mechanisms. In an attempt to explain the striking difference between the commonly observed elevation of RGC-32 level in a variety of diseases and the observed decline in pulmonary RGC-32 mRNA and protein in patients with SLD and IPF, the possibility was considered that the decrease in RGC-32 in pulmonary fibrosis might be part of a failing protective feedback loop in which lower RGC-32 levels represent the organism’s attempt to attenuate profibrotic signaling. To assess this possibility, germline-deficient (RGC-32–/–) mice were challenged with bleomycin. The expectation was that if RGC-32 is a profibrotic mediator as suggested by the studies of kidney fibrosis, then RGC-32–/– mice would be protected from bleomycin-induced fibrosis compared with their wild-type RGC-32+/+ strain background controls. However, RGC-32–/– mice were not only not protected from fibrosis, but accumulated significantly more collagen in response to bleomycin challenge, indicating that RGC-32 acts protectively against fibrosis in the lungs. Further supporting this notion, overexpression of RGC-32 attenuated TGF-β-induced upregulation of collagen in primary human lung fibroblast cultures.
Conclusion: These combined data from human patients, the animal model, and cultured primary fibroblasts indicate that RGC-32 protects from fibrosis in the lung and that its loss in patients with SLD and IPF allows for a more severe fibrosis. Therapeutic restoration of pulmonary RGC-32 levels may be beneficial for patients with pulmonary fibrosis.
To cite this abstract in AMA style:Atamas S, Rus V, Lockatell V, Rus H, Luzina I. Antifibrotic Regulation By Response Gene to Complement 32 Protein [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/antifibrotic-regulation-by-response-gene-to-complement-32-protein/. Accessed January 20, 2020.
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