Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling
Diabetic nephropathy (DN) is a chronic low-grade inflammatory disease. Oxidative stress and nuclear factor kappa B (NF-κB) signaling play an important role in the pathogenesis of DN. Short-chain fatty acids (SCFAs) produced from carbohydrate fermentation in the gastrointestinal tract exert positive...
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Series: | Oxidative Medicine and Cellular Longevity |
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doaj-d40433bcff3748818990f3d79f6bb6d52020-11-25T03:36:03ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942020-01-01202010.1155/2020/40748324074832Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB SignalingWei Huang0Yi Man1Chenlin Gao2Luping Zhou3Junling Gu4Huiwen Xu5Qin Wan6Yang Long7Li Chai8Youhua Xu9Yong Xu10Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaAffiliated Hospital of Southwest Medical University, Luzhou, Luzhou, Sichuan, 646000, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDepartment of Pathology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaFaculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, ChinaDepartment of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, ChinaDiabetic nephropathy (DN) is a chronic low-grade inflammatory disease. Oxidative stress and nuclear factor kappa B (NF-κB) signaling play an important role in the pathogenesis of DN. Short-chain fatty acids (SCFAs) produced from carbohydrate fermentation in the gastrointestinal tract exert positive regulatory effects on inflammation and kidney injuries. However, it is unclear whether SCFAs can prevent and ameliorate DN. In the present study, we evaluated the role and mechanism of the three main SCFAs (acetate, propionate, and butyrate) in high-fat diet (HFD) and streptozotocin- (STZ-) induced type2 diabetes (T2D) and DN mouse models and in high glucose-induced mouse glomerular mesangial cells (GMCs), to explore novel therapeutic strategies and molecular targets for DN. We found that exogenous SCFAs, especially butyrate, improved hyperglycemia and insulin resistance; prevented the formation of proteinuria and an increase in serum creatinine, urea nitrogen, and cystatin C; inhibited mesangial matrix accumulation and renal fibrosis; and blocked NF-κB activation in mice. SCFAs also inhibited high glucose-induced oxidative stress and NF-κB activation and enhanced the interaction between β-arrestin-2 and I-κBα in GMCs. Specifically, the beneficial effects of SCFAs were significantly facilitated by the overexpression GPR43 or imitated by a GPR43 agonist but were inhibited by siRNA-GPR43 in GMCs. These results support the conclusion that SCFAs, especially butyrate, partially improve T2D-induced kidney injury via GPR43-mediated inhibition of oxidative stress and NF-κB signaling, suggesting SCFAs may be potential therapeutic agents in the prevention and treatment of DN.http://dx.doi.org/10.1155/2020/4074832 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei Huang Yi Man Chenlin Gao Luping Zhou Junling Gu Huiwen Xu Qin Wan Yang Long Li Chai Youhua Xu Yong Xu |
spellingShingle |
Wei Huang Yi Man Chenlin Gao Luping Zhou Junling Gu Huiwen Xu Qin Wan Yang Long Li Chai Youhua Xu Yong Xu Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling Oxidative Medicine and Cellular Longevity |
author_facet |
Wei Huang Yi Man Chenlin Gao Luping Zhou Junling Gu Huiwen Xu Qin Wan Yang Long Li Chai Youhua Xu Yong Xu |
author_sort |
Wei Huang |
title |
Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling |
title_short |
Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling |
title_full |
Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling |
title_fullStr |
Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling |
title_full_unstemmed |
Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-κB Signaling |
title_sort |
short-chain fatty acids ameliorate diabetic nephropathy via gpr43-mediated inhibition of oxidative stress and nf-κb signaling |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2020-01-01 |
description |
Diabetic nephropathy (DN) is a chronic low-grade inflammatory disease. Oxidative stress and nuclear factor kappa B (NF-κB) signaling play an important role in the pathogenesis of DN. Short-chain fatty acids (SCFAs) produced from carbohydrate fermentation in the gastrointestinal tract exert positive regulatory effects on inflammation and kidney injuries. However, it is unclear whether SCFAs can prevent and ameliorate DN. In the present study, we evaluated the role and mechanism of the three main SCFAs (acetate, propionate, and butyrate) in high-fat diet (HFD) and streptozotocin- (STZ-) induced type2 diabetes (T2D) and DN mouse models and in high glucose-induced mouse glomerular mesangial cells (GMCs), to explore novel therapeutic strategies and molecular targets for DN. We found that exogenous SCFAs, especially butyrate, improved hyperglycemia and insulin resistance; prevented the formation of proteinuria and an increase in serum creatinine, urea nitrogen, and cystatin C; inhibited mesangial matrix accumulation and renal fibrosis; and blocked NF-κB activation in mice. SCFAs also inhibited high glucose-induced oxidative stress and NF-κB activation and enhanced the interaction between β-arrestin-2 and I-κBα in GMCs. Specifically, the beneficial effects of SCFAs were significantly facilitated by the overexpression GPR43 or imitated by a GPR43 agonist but were inhibited by siRNA-GPR43 in GMCs. These results support the conclusion that SCFAs, especially butyrate, partially improve T2D-induced kidney injury via GPR43-mediated inhibition of oxidative stress and NF-κB signaling, suggesting SCFAs may be potential therapeutic agents in the prevention and treatment of DN. |
url |
http://dx.doi.org/10.1155/2020/4074832 |
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