Kaempferol attenuates streptozotocin-induced diabetic nephropathy by downregulating TRAF6 expression: The role of TRAF6 in diabetic nephropathy.

Kaempferia rhizome is a famous traditional herbal medical in tropical and subtropical areas. Kaempferol (KPF) is one of the main bioactive compounds in Kaempferia rhizome, with anti-oxidant/anti-inflammatory effects demonstrated in various disease models, including cancers, obesity and diabetes. Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). TRAF6 functions as a signal transducer in toll-like receptor 4 and NF-κB pro-inflammatory signaling pathway. We aimed at investigate whether KPF is able to mitigate inflammatory responses by regulating TRAF6 in DN. C57BL/6 mice were injected with streptozotocin to induce type 1 DN. NRK-52E, a tubular epithelial cell line, was used for in vitro analysis. TRAF6 was knockdown using siRNA in vitro and AAV2/2-shRNA in vivo. The anti-DN and inflammatory effects of KPF or knockdown of TRAF6 were evaluated by investigating renal filtration index, pathological changes of kidney tissue. Proinflammatory cytokine levels were detected using ELISA. NF-κB pathway and protein levels of related pathways were detected through Western blot. KPF significantly reduced renal inflammation, fibrosis, and kidney dysfunction in diabetic mice. These effects were associated with a downregulation of TRAF6 in diabetic mouse kidneys, indicating the potential role of TRAF6. Knockdown of TRAF6 in mice through AAV2-shTRAF6 confirmed the importance of TRAF6 in DN. In vitro, treatment of KPF in NRK-52E cells attenuated high glucose (HG)-induced inflammatory and fibrogenic responses, associated with downregulated TRAF6 expression. The conclusion was further confirmed in NRK-52E cells by knocking down the expression and by overexpression of TRAF6. Our findings provide direct evidence that TRAF6 mediates diabetes-induced inflammation leading to renal dysfunction. We also show that KPF is a potential therapeutic agent to reduce inflammatory responses in DN. Also, TRAF6 may represent an interesting target to combat DN. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Wu Luo, Xiaojun Chen, Lin Ye, Xuemei Chen, Wenjing Jia, Yanni Zhao, Aleksandr V Samorodov, Yali Zhang, Xueting Hu, Fei Zhuang, Jianchang Qian, Chao Zheng, Guang Liang, Yi Wang. Kaempferol attenuates streptozotocin-induced diabetic nephropathy by downregulating TRAF6 expression: The role of TRAF6 in diabetic nephropathy. Journal of ethnopharmacology. 2021 Mar 25;268:113553

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PMID: 33152432

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