Wogonin Upregulates SOCS3 to Alleviate the Injury in Diabetic Nephropathy by Inhibiting TLR4-mediated JAK/STAT/AIM2 Signaling Pathway

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2024 Jun 6

PMID 38844873

Authors

Yufeng Liu

Mengbi Zhang

Lu Zeng

Yanhong Lai

Songzhao Wu

Xiaoyan Su

Affiliations

Soon will be listed here.

Abstract

Background: Diabetic nephropathy (DN) is a life-threatening renal disease and needs urgent therapies. Wogonin is renoprotective in DN. This study aimed to explore the mechanism of how wogonin regulated high glucose (HG)-induced renal cell injury.

Methods: Diabetic mice (db/db), control db/m mice, and normal glucose (NG)- or HG-treated human tubule epithelial cells (HK-2) were used to evaluate the levels of suppressor of cytokine signaling 3 (SOCS3), Toll-like receptor 4 (TLR4), inflammation and fibrosis. Lentivirus was used to regulate SOCS3 and TLR4 expressions. After oral gavage of wogonin (10 mg/kg) or vehicle in db/db mice, histological morphologies, blood glucose, urinary protein, serum creatinine values (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH), and reactive oxygen species (ROS) were assessed. RT-qPCR and Western blot evaluated inflammation and fibrosis-related molecules.

Results: HG exposure induced high blood glucose, severe renal injuries, high serumal Src and BUN, low SOD and GSH, and increased ROS. HG downregulated SOCS3 but upregulated TLR4 and JAK/STAT, fibrosis, and inflammasome-related proteins. Wogonin alleviated HG-induced renal injuries by decreasing cytokines, ROS, Src, and MDA and increasing SOD and GSH. Meanwhile, wogonin upregulated SOCS3 and downregulated TLR4 under HG conditions. Wogonin-induced SOCS3 overexpression directly decreased TLR4 levels and attenuated JAK/STAT signaling pathway-related inflammation and fibrosis, but SOCS3 knockdown significantly antagonized the protective effects of wogonin. However, TLR4 knockdown diminished SOCS3 knockdown-induced renal injuries.

Conclusion: Wogonin attenuates renal inflammation and fibrosis by upregulating SOCS3 to inhibit TLR4 and JAK/STAT pathway.

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References

Zhang H, Wang Y, Li S, Tang X, Liang R, Yang X . SOCS3 protects against neonatal necrotizing enterocolitis via suppressing NLRP3 and AIM2 inflammasome activation and p65 nuclear translocation. Mol Immunol. 2020; 122:21-27. DOI: 10.1016/j.molimm.2020.03.019. View

Duan W, Xia Z, Liu M, Sun Q, Lei S, Wu X . Protective effects of SOCS3 overexpression in high glucose‑induced lung epithelial cell injury through the JAK2/STAT3 pathway. Mol Med Rep. 2017; 16(3):2668-2674. PMC: 5547984. DOI: 10.3892/mmr.2017.6941. View

Zhang S, Xu L, Liang R, Yang C, Wang P . Baicalin suppresses renal fibrosis through microRNA-124/TLR4/NF-κB axis in streptozotocin-induced diabetic nephropathy mice and high glucose-treated human proximal tubule epithelial cells. J Physiol Biochem. 2020; 76(3):407-416. DOI: 10.1007/s13105-020-00747-z. View

Liu J, Zhang L, Huang Y, Li X, Liu Y, Zhang S . Epsin1-mediated exosomal sorting of Dll4 modulates the tubular-macrophage crosstalk in diabetic nephropathy. Mol Ther. 2023; 31(5):1451-1467. PMC: 10188907. DOI: 10.1016/j.ymthe.2023.03.027. View

Mogensen C, Christensen C, Vittinghus E . The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes. 1983; 32 Suppl 2:64-78. DOI: 10.2337/diab.32.2.s64. View

Wada J, Makino H . Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2012; 124(3):139-52. DOI: 10.1042/CS20120198. View

Xu Y, Yang B, Hu Y, Lu L, Lu X, Wang J . Wogonin prevents TLR4-NF-κB-medicated neuro-inflammation and improves retinal ganglion cells survival in retina after optic nerve crush. Oncotarget. 2016; 7(45):72503-72517. PMC: 5341925. DOI: 10.18632/oncotarget.12700. View

Leite A, Aragao D, Nogueira M, Pereira R, Jara Z, Fiorino P . Modulation of renin angiotensin system components by high glucose levels in the culture of collecting duct cells. J Cell Physiol. 2019; 234(12):22809-22818. DOI: 10.1002/jcp.28845. View

Zhou Z, Zhou X, Dong Y, Li M, Xu Y . Formononetin ameliorates high glucose‑induced endothelial dysfunction by inhibiting the JAK/STAT signaling pathway. Mol Med Rep. 2019; 20(3):2893-2901. DOI: 10.3892/mmr.2019.10512. View

10.

Sagoo M, Gnudi L . Diabetic Nephropathy: An Overview. Methods Mol Biol. 2019; 2067:3-7. DOI: 10.1007/978-1-4939-9841-8_1. View

11.

Haider M, Albaqsumi Z, Al-Mulla F, Ahmad R, Al-Rashed F . SOCS3 Regulates Dectin-2-Induced Inflammation in PBMCs of Diabetic Patients. Cells. 2022; 11(17). PMC: 9454960. DOI: 10.3390/cells11172670. View

12.

Wolf G . New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest. 2004; 34(12):785-96. DOI: 10.1111/j.1365-2362.2004.01429.x. View

13.

Yoshimura A, Nishinakamura H, Matsumura Y, Hanada T . Negative regulation of cytokine signaling and immune responses by SOCS proteins. Arthritis Res Ther. 2005; 7(3):100-10. PMC: 1174965. DOI: 10.1186/ar1741. View

14.

Nam K, Chae S, Song H, Mar W, Han M . The role of wogonin in controlling SOCS3 expression in neuronal cells. Biochem Biophys Res Commun. 2014; 450(4):1518-24. DOI: 10.1016/j.bbrc.2014.07.018. View

15.

Zhu L, Wang H, Tang T . Effects of miR-195 on diabetic nephropathy rats through targeting TLR4 and blocking NF-κB pathway. Eur Rev Med Pharmacol Sci. 2021; 25(3):1522-1529. DOI: 10.26355/eurrev_202102_24860. View

16.

Zoja C, Xinaris C, Macconi D . Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets. Front Pharmacol. 2021; 11:586892. PMC: 7845653. DOI: 10.3389/fphar.2020.586892. View

17.

Lontchi-Yimagou E, Sobngwi E, Matsha T, Kengne A . Diabetes mellitus and inflammation. Curr Diab Rep. 2013; 13(3):435-44. DOI: 10.1007/s11892-013-0375-y. View

18.

Liu T, Zheng W, Wang L, Wang L, Zhang Y . TLR4/NF-κB Signaling Pathway Participates in the Protective Effects of Apocynin on Gestational Diabetes Mellitus Induced Placental Oxidative Stress and Inflammation. Reprod Sci. 2020; 27(2):722-730. DOI: 10.1007/s43032-019-00078-5. View

19.

Wang W, Xia T, Yu X . Wogonin suppresses inflammatory response and maintains intestinal barrier function via TLR4-MyD88-TAK1-mediated NF-κB pathway in vitro. Inflamm Res. 2015; 64(6):423-31. DOI: 10.1007/s00011-015-0822-0. View

20.

Brosius 3rd F . New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy. Rev Endocr Metab Disord. 2008; 9(4):245-54. PMC: 3776415. DOI: 10.1007/s11154-008-9100-6. View