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Dae-Kee Kim 1 Article
Diabetes, Obesity and Metabolism
EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
Kyung Bong Ha, Weerapon Sangartit, Ah Reum Jeong, Eun Soo Lee, Hong Min Kim, Soyeon Shim, Upa Kukongviriyapan, Dae-Kee Kim, Eun Young Lee, Choon Hee Chung
Endocrinol Metab. 2022;37(1):96-111.   Published online February 28, 2022
DOI: https://doi.org/10.3803/EnM.2021.1305
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  • 3 Web of Science
  • 3 Crossref
AbstractAbstract PDFPubReader   ePub   
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.

Citations

Citations to this article as recorded by  
  • TGF-β signaling in health, disease, and therapeutics
    Ziqin Deng, Tao Fan, Chu Xiao, He Tian, Yujia Zheng, Chunxiang Li, Jie He
    Signal Transduction and Targeted Therapy.2024;[Epub]     CrossRef
  • Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols
    Qi Jin, Tongtong Liu, Yuan Qiao, Donghai Liu, Liping Yang, Huimin Mao, Fang Ma, Yuyang Wang, Liang Peng, Yongli Zhan
    Frontiers in Immunology.2023;[Epub]     CrossRef
  • Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis
    Kyung Bong Ha, Eun Soo Lee, Na Won Park, Su Ho Jo, Soyeon Shim, Dae-Kee Kim, Chan Mug Ahn, Choon Hee Chung
    Diabetes & Metabolism Journal.2023; 47(4): 500.     CrossRef
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