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.

• Authors: 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
• Journal: Endocrinology and metabolism (Seoul, Korea) (Endocrinol Metab (Seoul)) Vol. 37 Issue 1 Pg. 96-111 (02 2022) ISSN: 2093-5978 [Electronic] Korea (South)
• PMID: 35255604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Triazoles
• vactosertib

Topics

• Aniline Compounds
• Animals
• Diabetes Mellitus, Experimental (complications, drug therapy, metabolism)
• Diabetic Nephropathies (drug therapy, prevention & control)
• Inflammation (complications)
• Mice
• Triazoles (therapeutic use)