EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
- 주제(키워드) Diabetic nephropathies , Glomerular mesangial cells , Podocytes , Transforming growth factor beta , Activin receptor-like kinase 5
- 주제(기타) Endocrinology & Metabolism
- 설명문(일반) [Ha, Kyung Bong; Lee, Eun Soo; Kim, Hong Min; Chung, Choon Hee] Yonsei Univ, Dept Internal Med, Wonju Coll Med, 20 Ilsan Ro, Wonju 26426, South Korea; [Sangartit, Weerapon; Kukongyiriyapan, Upa] Khon Kaen Univ, Fac Med, Dept Physiol, Khon Kaen, Thailand; [Sangartit, Weerapon; Kukongyiriyapan, Upa] Khon Kaen Univ, Cardiovasc Res Grp, Khon Kaen, Thailand; [Jeong, Ah Reum; Lee, Eun Young] Soonchunhyang Univ, Coll Med, Dept Internal Med, Cheonan, South Korea; [Jeong, Ah Reum; Lee, Eun Young] Soonchunhyang Univ, Coll Med, Inst Tissue Regenerat, Cheonan, South Korea; [Lee, Eun Soo; Chung, Choon Hee] Yonsei Univ, Inst Genet Cohort, Wonju Coll Med, Wonju, South Korea; [Shim, Soyeon; Kim, Dae-Kee] Ewha Womans Univ, Dept Pharm, Coll Pharm, Seoul, South Korea
- 등재 SCIE, SCOPUS, KCI등재
- OA유형 Green Published, gold
- 발행기관 KOREAN ENDOCRINE SOC
- 발행년도 2022
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000190878
- 본문언어 영어
- Published As https://doi.org/10.3803/EnM.2021.1305
- PubMed https://pubmed.ncbi.nlm.nih.gov/35255604
초록/요약
Background: Diabetic nephropathy (DN) is characterized by albuminuria and accumulation of extracellular matrix (ECM) in kidney. Transforming growth factor-f3 (TGF-f3) plays a central role in promoting ECM accumulation. We aimed to examine the effects of EW-7197, an inhibitor of TGF-f3 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-f3 (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-f3 signaling pathway. Treatment with EW-7197 significantly inhibited TGF-f3 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-f3 signaling, thereby retarding the progression of DN. Our study supports EW-7197 as a therapeutically beneficial compound to treat DN.
more