- Diabetes, Obesity and Metabolism
- EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
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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
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Endocrinol Metab. 2022;37(1):96-111. Published online February 28, 2022
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DOI: https://doi.org/10.3803/EnM.2021.1305
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 Abstract
 PDF PubReader  ePub  Crossref - TDM
- 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.
- Diabetes, Obesity and Metabolism
- Tetrahydrocurcumin Ameliorates Kidney Injury and High Systolic Blood Pressure in High-Fat Diet-Induced Type 2 Diabetic Mice
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Weerapon Sangartit, Kyung Bong Ha, Eun Soo Lee, Hong Min Kim, Upa Kukongviriyapan, Eun Young Lee, Choon Hee Chung
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Endocrinol Metab. 2021;36(4):810-822. Published online August 27, 2021
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DOI: https://doi.org/10.3803/EnM.2021.988
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Abstract
PDFPubReader ePub Crossref - TDM
- Background
Activation of the intrarenal renin-angiotensin system (RAS) is implicated in the pathogenesis of kidney injury and hypertension. We aimed to investigate the protective effect of tetrahydrocurcumin (THU) on intrarenal RAS expression, kidney injury, and systolic blood pressure (SBP) in high-fat diet (HFD)-induced type 2 diabetic mice.
Methods
Eight-week-old male mice were fed a regular diet (RD) or HFD for 12 weeks, and THU (50 or 100 mg/kg/day) was intragastrically administered with HFD. Physiological and metabolic changes were monitored and the expression of RAS components and markers of kidney injury were assessed.
Results
HFD-fed mice exhibited hyperglycemia, insulin resistance, and dyslipidemia compared to those in the RD group (P<0.05). Kidney injury in these mice was indicated by an increase in the ratio of albumin to creatinine, glomerular hypertrophy, and the effacement of podocyte foot processes. Expression of intrarenal angiotensin-converting enzyme, angiotensin II type I receptor, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4, and monocyte chemoattractant protein-1 was also markedly increased in HFD-fed mice. HFD-fed mice exhibited elevated SBP that was accompanied by an increase in the wall thickness and vascular cross-sectional area (P<0.05), 12 weeks post-HFD consumption. Treatment with THU (100 mg/kg/day) suppressed intrarenal RAS activation, improved insulin sensitivity, and reduced SBP, thus, attenuating kidney injury in these mice.
Conclusion
THU alleviated kidney injury in mice with HFD-induced type 2 diabetes, possibly by blunting the activation of the intrarenal RAS/nicotinamide adenine dinucleotide phosphate oxidase IV (NOX4)/monocyte chemoattractant protein 1 (MCP-1) axis and by lowering the high SBP.
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Citations
Citations to this article as recorded by  - The Development of Dyslipidemia in Chronic Kidney Disease and Associated Cardiovascular Damage, and the Protective Effects of Curcuminoids
Zeltzin Alejandra Ceja-Galicia, Ana Karina Aranda-Rivera, Isabel Amador-Martínez, Omar Emiliano Aparicio-Trejo, Edilia Tapia, Joyce Trujillo, Victoria Ramírez, José Pedraza-Chaverri
Foods.2023; 12(5): 921. CrossRef - An examination of the protective effects and molecular mechanisms of curcumin, a polyphenol curcuminoid in diabetic nephropathy
Xiaoyu Zhu, Xingli Xu, Chigang Du, Yanping Su, Lixue Yin, Xiaoqiu Tan, Hui Liu, Yiru Wang, Lei Xu, Xinghua Xu
Biomedicine & Pharmacotherapy.2022; 153: 113438. CrossRef
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