Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease
Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative...
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Frontiers Media S.A.
2021-06-01
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Series: | Frontiers in Pharmacology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.680336/full |
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doaj-7beeec539874415388322609713d303f |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mei Jing Mei Jing Yun Cen Fangfang Gao Ting Wang Jinxin Jiang Qianqian Jian Liangmiao Wu Liangmiao Wu Baojian Guo Fangcheng Luo Fangcheng Luo Gaoxiao Zhang Ying Wang Lipeng Xu Zaijun Zhang Yewei Sun Yuqiang Wang |
spellingShingle |
Mei Jing Mei Jing Yun Cen Fangfang Gao Ting Wang Jinxin Jiang Qianqian Jian Liangmiao Wu Liangmiao Wu Baojian Guo Fangcheng Luo Fangcheng Luo Gaoxiao Zhang Ying Wang Lipeng Xu Zaijun Zhang Yewei Sun Yuqiang Wang Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease Frontiers in Pharmacology diabetic kidney disease nephroprotection metabolic abnormalities oxidative stress mitochondrial function |
author_facet |
Mei Jing Mei Jing Yun Cen Fangfang Gao Ting Wang Jinxin Jiang Qianqian Jian Liangmiao Wu Liangmiao Wu Baojian Guo Fangcheng Luo Fangcheng Luo Gaoxiao Zhang Ying Wang Lipeng Xu Zaijun Zhang Yewei Sun Yuqiang Wang |
author_sort |
Mei Jing |
title |
Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease |
title_short |
Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease |
title_full |
Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease |
title_fullStr |
Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease |
title_full_unstemmed |
Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease |
title_sort |
nephroprotective effects of tetramethylpyrazine nitrone tbn in diabetic kidney disease |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2021-06-01 |
description |
Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-β-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2′-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2′-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD. |
topic |
diabetic kidney disease nephroprotection metabolic abnormalities oxidative stress mitochondrial function |
url |
https://www.frontiersin.org/articles/10.3389/fphar.2021.680336/full |
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doaj-7beeec539874415388322609713d303f2021-06-24T08:29:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-06-011210.3389/fphar.2021.680336680336Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney DiseaseMei Jing0Mei Jing1Yun Cen2Fangfang Gao3Ting Wang4Jinxin Jiang5Qianqian Jian6Liangmiao Wu7Liangmiao Wu8Baojian Guo9Fangcheng Luo10Fangcheng Luo11Gaoxiao Zhang12Ying Wang13Lipeng Xu14Zaijun Zhang15Yewei Sun16Yuqiang Wang17Institute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaDepartment of Gerontology, The First Affiliated Hospital of Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaDepartment of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaDepartment of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, MacaoInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaInstitute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Jinan University, Guangzhou, ChinaDiabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-β-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2′-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2′-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD.https://www.frontiersin.org/articles/10.3389/fphar.2021.680336/fulldiabetic kidney diseasenephroprotectionmetabolic abnormalitiesoxidative stressmitochondrial function |