Baicalin Alleviates Oxidative Stress and Inflammation in Diabetic Nephropathy via Nrf2 and MAPK Signaling Pathway

Leyi Ma; Fan Wu; Qingqing Shao; Guang Chen; Lijun Xu; Fuer Lu

doi:10.2147/DDDT.S319260

Baicalin Alleviates Oxidative Stress and Inflammation in Diabetic Nephropathy via Nrf2 and MAPK Signaling Pathway

Drug Des Devel Ther. 2021 Jul 21:15:3207-3221. doi: 10.2147/DDDT.S319260. eCollection 2021.

Authors

Leyi Ma^#¹, Fan Wu^#¹, Qingqing Shao¹, Guang Chen², Lijun Xu¹, Fuer Lu¹

Affiliations

¹ Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
² Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.

^# Contributed equally.

Abstract

Background: Oxidative stress and inflammation play essential roles in the development and progression of diabetic nephropathy (DN). Baicalin (BAI), a natural flavonoid, has been showed to have a renoprotective effect in various renal diseases. However, its underlying mechanisms in DN remain unclear. In this study, we explored the potential effects and underlying mechanisms of BAI on DN using a spontaneous DN model.

Methods: The protective effects of BAI on DN have been evaluated by detecting DN-related biochemical indicators, kidney histopathology and cell apoptosis. After that, we examined the level of renal oxidative stress and inflammation to explain BAI's renoprotective effects. Then, Nrf2 pathway was tested to clarify its antioxidant activity, and kidney transcriptomics was conducted to elucidate its anti-inflammatory activity. Finally, Western blot was applied for final mechanism verification.

Results: Our results found that BAI effectively ameliorated diabetic conditions, proteinuria, renal histopathological changes and cell apoptosis in DN. BAI significantly improved the kidney levels of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT), and reduced malondialdehyde (MDA) level. Meanwhile, the infiltration of inflammatory cells including T-lymphocytes, T-helper cells, neutrophils and macrophages, and the mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, MCP-1 and TNFα) were also obviously inhibited by BAI. Afterward, Western blot found that BAI significantly activated Nrf2 signaling and increased the expression of downstream antioxidant enzymes (HO-1, NQO-1). Kidney transcriptomics revealed that the inhibition of MAPK signaling pathway may contribute to BAI's anti-inflammatory activity, which has also been verified in later experiment. BAI treatment did obviously inhibit the activation of canonical pro-inflammatory signaling pathway MAPK family, such as Erk1/2, JNK and P38.

Conclusion: In summary, our data demonstrated that BAI can treat DN by alleviating oxidative stress and inflammation, and its underlying mechanisms were associated with the activation of Nrf2-mediated antioxidant signaling pathway and the inhibition of MAPK-mediated inflammatory signaling pathway.

Keywords: MAPK; Nrf2; baicalin; diabetic nephropathy; inflammation; oxidative stress.

MeSH terms

Animals
Apoptosis / drug effects
Diabetic Nephropathies / drug therapy*
Diabetic Nephropathies / metabolism
Diabetic Nephropathies / pathology
Flavonoids / pharmacology*
Flavonoids / therapeutic use
Inflammation / drug therapy*
MAP Kinase Signaling System / physiology*
Male
Mice
NF-E2-Related Factor 2 / physiology*
Oxidative Stress / drug effects*

Substances

Flavonoids
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
baicalin

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81974567), and TCM Modernization Research of National Key Research and Development Program (No. 2018YFC1704202).