Abstract: PO2488
First-in-Class PRS Inhibitor DWN12088 Ameliorates Folic Acid-Induced Kidney Fibrosis
Session Information
- CKD: Metabolism, Epigenetics, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Son, Seung Seob, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
- Lee, Seong Woo, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
- Park, Mi Ju, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
- Choi, Min Sun, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
- Lee, Eun Soo, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea (the Republic of)
- Kang, Jeong suk, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
- Chung, Choon Hee, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea (the Republic of)
- Park, Joon Seok, Daewoong Pharmaceutical Co., Ltd., Drug Discovery Center, Yongin, Korea (the Republic of)
- Lee, Eun Young, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
Background
Fibrosis is characterized by the upregulated extracelluar matrix (ECM), which drives organ damage and abnormal cell proliferation. According to recent studies, PRS (prolyl- tRNA synthetase) is known to play a role in synthesizing collagen during ECM components. It has been reported that PRS is greatly increased in the lung and liver fibrosis animal model, but the role of PRS in the renal fibrosis model has not been elucidated.
Methods
In this study, we investigated the protective effect of novel PRS inhibitor (Daewoong Pharmaceutical Co., Ltd, Korea), in folic acid (FA)-induced kidney fibrosis and aimed to determine whether this role depends on the inhibition of mitochondria dysfunction and the STAT3 signaling pathway. Renal fibrosis was induced by FA (250 mg/kg) intraperitoneal injection in C57BL/6 mice. DWN12088 (10, 30 mg/kg) was administered by intraperitoneal daily injection for 4 weeks. Histological changes were examined by Masson's trichrome staining. The expression of ECM markers was evaluated by immunohistochemistry, western blot analysis and real time-PCR. Mitochondria was also examined by electron microscopy.
Results
FA induced renal fibrosis and mitochondria dysfunction and upregulated PRS expression. When the FA induced decreased weight in mice, there was an effect on body weight by administering the DWN12088. We also examined the blood urea nitrogen (BUN), serum creatinine (Cr), creatinine clearance (CCr) and urine protein creatinine ratio (UPCR) levels. DWN12088 attenuated the levels of clinical data of renal injury (it decreased the BUN levels, Cr levels and UPCR levels, and increased the CCr levels). The administration of DWN12088 decreased the PRS levels and improved FA-induced renal fibrosis and mitochondria. Moreover, DWN12088 effectively inhibited the ECM markers (FN and Collagen 1A1) and the levels of SIRT1/STAT3 induced by TGF- β1 induced fibrotic condition in HK-2 cells. DWN12088 also improved mitochondria function in HK-2 cells.
Conclusion
This study provides evidence for the detrimental role of upregulated PRS in the pathogenesis of renal fibrosis. The findings highlight a DWN12088 that improves renal fibrosis and mitochondria dysfunction. As a result, blockade of PRS is a potential therapeutic intervention to prevent renal fibrosis (NRF-2020R1A2C2003438).
Funding
- Government Support – Non-U.S.