EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
- 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.
- All Author(s)
- K. B. Ha
; W. Sangartit
; A. R. Jeong
; E. S. Lee
; H. M. Kim
; S. Shim
; U. Kukongviriyapan
; D. K. Kim
; E. Y. Lee
; C. H. Chung
- Issued Date
- 2022
- Type
- Article
- Keyword
- Diabetic nephropathies; Glomerular mesangial cells; Podocytes; Transforming growth factor beta; Activin receptor-like kinase 5
- Publisher
- 대한내분비학회
- ISSN
- 2093-596X
- Citation Title
- Endocrinology and Metabolism
- Citation Volume
- 37
- Citation Number
- 1
- Citation Start Page
- 96
- Citation End Page
- 111
- Language(ISO)
- eng
- DOI
- 10.3803/EnM.2021.1305
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/2328
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