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EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
- Title
- EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
- Authors
- Ha K.B.; Sangartit W.; Jeong A.R.; Lee E.S.; Kim H.M.; Shim S.; Kukongviriyapan U.; Kim D.-K.; Lee E.Y.; Chung C.H.
- Ewha Authors
- 심소연
- SCOPUS Author ID
- 심소연
- Issue Date
- 2022
- Journal Title
- Endocrinology and Metabolism
- ISSN
- 2093-596X
- Citation
- Endocrinology and Metabolism vol. 37, no. 1, pp. 96 - 111
- Keywords
- Activin receptor-like kinase 5; Diabetic nephropathies; Glomerular mesangial cells; Podocytes; Transforming growth factor beta
- Publisher
- Korean Endocrine Society
- Indexed
- SCIE; SCOPUS; KCI
- Document Type
- Article
- Abstract
- Background: Diabetic nephropathy (DN) is characterized by albuminuria and accumulation of extracellular matrix (ECM) in kidney. Transforming growth factor-β (TGF-β) plays a central role in promoting ECM accumulation. We aimed to examine the effects of EW-7197, an inhibitor of TGF-β type 1 receptor kinase (ALK5), in retarding the progression of DN, both in vivo, using a diabetic mouse model (db/db mice), and in vitro, in podocytes and mesangial cells. Methods: In vivo study: 8-week-old db/db mice were orally administered EW-7197 at a dose of 5 or 20 mg/kg/day for 10 weeks. Metabolic parameters and renal function were monitored. Glomerular histomorphology and renal protein expression were evaluated by histochemical staining and Western blot analyses, respectively. In vitro study: DN was induced by high glucose (30 mM) in podocytes and TGF-β (2 ng/mL) in mesangial cells. Cells were treated with EW-7197 (500 nM) for 24 hours and the mechanism associated with the attenuation of DN was investigated. Results: Enhanced albuminuria and glomerular morphohistological changes were observed in db/db compared to that of the nondiabetic (db/m) mice. These alterations were associated with the activation of the TGF-β signaling pathway. Treatment with EW-7197 significantly inhibited TGF-β signaling, inflammation, apoptosis, reactive oxygen species, and endoplasmic reticulum stress in diabetic mice and renal cells. Conclusion: EW-7197 exhibits renoprotective effect in DN. EW-7197 alleviates renal fibrosis and inflammation in diabetes by inhibiting downstream TGF-β signaling, thereby retarding the progression of DN. Our study supports EW-7197 as a therapeutically beneficial compound to treat DN. Copyright © 2022 Korean Endocrine Society.
- DOI
- 10.3803/ENM.2021.1305
- Appears in Collections:
- 의과대학 > 의학과 > Journal papers
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