In:
Endocrinology and Metabolism, Korean Endocrine Society, Vol. 37, No. 1 ( 2022-02-28), p. 96-111
Kurzfassung:
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 〈 i 〉 in vivo 〈 /i 〉 , using a diabetic mouse model ( 〈 i 〉 db/db 〈 /i 〉 mice), and 〈 i 〉 in vitro 〈 /i 〉 , in podocytes and mesangial cells.Methods: 〈 i 〉 In vivo 〈 /i 〉 study: 8-week-old 〈 i 〉 db/db 〈 /i 〉 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. 〈 i 〉 In vitro 〈 /i 〉 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 〈 i 〉 db/db 〈 /i 〉 compared to that of the nondiabetic ( 〈 i 〉 db/m 〈 /i 〉 ) 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.
Materialart:
Online-Ressource
ISSN:
2093-596X
,
2093-5978
DOI:
10.3803/EnM.2021.1305
Sprache:
Englisch
Verlag:
Korean Endocrine Society
Publikationsdatum:
2022
ZDB Id:
2802452-7
