Mechanism of dioscin ameliorating renal fibrosis through NF-κB signaling pathway-mediated inflammatory response

Wang,Yang; Liu,Peng; Ma,Guijie; Wu,Chenguang; Zhu,Wenhui; Sun,Pengce; Lu,Wenya; Yang,Xinyu; Zhang,Yilun; Liu,Na; Li,Ping

doi:10.3892/mmr.2023.12980

Mechanism of dioscin ameliorating renal fibrosis through NF-κB signaling pathway-mediated inflammatory response

Authors:
- Yang Wang
- Peng Liu
- Guijie Ma
- Chenguang Wu
- Wenhui Zhu
- Pengce Sun
- Wenya Lu
- Xinyu Yang
- Yilun Zhang
- Na Liu
- Ping Li
View Affiliations

Affiliations: Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, Heilongjiang 150036, P.R. China, Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Shunyi, Beijing 101300, P.R. China, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150036, P.R. China, Beijing Key Lab for Immune‑Mediated Inflammatory Diseases, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
Published online on: March 22, 2023 https://doi.org/10.3892/mmr.2023.12980
Article Number: 93
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Dioscin (DIS) is a natural compound derived from Chinese herbal medicine. In recent years, multiple studies have reported that DIS has immunoregulation, anti‑fibrosis, anti‑inflammation, anti‑viral and anti‑tumor effects. However, the mechanism by which DIS ameliorates renal fibrosis and inflammation remains to be elucidated. The aim of the present study was to investigate the role of DIS in renal fibrosis and inflammation and to explore its underlying mechanism. It used network pharmacology to predict the targets of DIS for the treatment of renal interstitial fibrosis. The present study was performed using unilateral ureteral obstruction mice and HK‑2 cells in vivo and in vitro. The mice were treated with different doses of DIS. Kidney tissues were collected for histopathology staining, western blotting, immunohistochemistry staining and reverse transcription‑quantitative (RT‑q) PCR. TGF‑β1 (2 ng/ml) was used to induce renal fibrosis in the cells. Then, cells were respectively treated with DIS (3.125, 6.25, 12.5 µM) and Bay11‑7082 (an inhibitor of NF‑κB p65 nuclear transcription, 1 µM) for another 24 h. The expressions of inflammatory factors and NF‑κB pathway proteins were detected by immunofluorescence, ELISA, western blotting and RT‑qPCR. DIS alleviated renal injury in the UUO mice. Mechanistically, DIS not only decreased the expressions of inflammatory factors including IL‑1β, NOD‑like receptor thermal protein domain associated protein 3, monocyte chemotactic protein 1, IL‑6, TNF‑α and IL‑18 but also reduced the level of phosphorylation of NF‑κB p65 in vivo and in vitro, which was similar to the impact of Bay11‑7082. DIS ameliorated renal fibrosis by inhibiting the NF‑κB signaling pathway‑mediated inflammatory response, which may be a therapeutic pathway for delaying chronic kidney disease.

View Figures

View References

1	Ruiz-Ortega M, Rayego-Mateos S, Lamas S, Ortiz A and Rodrigues-Diez RR: Targeting the progression of chronic kidney disease. Nat Rev Nephrol. 16:269–288. 2020. View Article : Google Scholar : PubMed/NCBI
2	Panizo S, Martinez-Arias L, Alonso-Montes C, Cannata P, Martín-Carro B, Fernández-Martín JL, Naves-Díaz M, Carrillo-López N and Cannata-Andía JB: Fibrosis in chronic kidney disease: Pathogenesis and consequences. Int J Mol Sci. 22:4082021. View Article : Google Scholar : PubMed/NCBI
3	Liu Y: Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 7:684–696. 2011. View Article : Google Scholar : PubMed/NCBI
4	Yuan Q and Liu YH: Recent advances on understanding of the cellular and molecular mechisms of renal fibrosis. J Anhui Univ Nat Sci Ed. 42:115–124. 2018.(In Chinese).
5	Li R, Guo Y, Zhang Y, Zhang X, Zhu L and Yan T: Salidroside ameliorates renal interstitial fibrosis by inhibiting the TLR4/NF-κB and MAPK signaling pathways. Int J Mol Sci. 20:11032019. View Article : Google Scholar : PubMed/NCBI
6	Simões e Silva AC, Silveira KD, Ferreira AJ and Teixeira MM: ACE2, angiotensin-(1–7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol. 169:477–492. 2013. View Article : Google Scholar : PubMed/NCBI
7	Zhang M and Zhang S: T cells in fibrosis and fibrotic diseases. Front Immunol. 11:11422020. View Article : Google Scholar : PubMed/NCBI
8	Tang PMK, Nikolic-Paterson DJ and Lan HY: Macrophages: Versatile players in renal inflammation and fibrosis. Nat Rev Nephrol. 15:144–158. 2019. View Article : Google Scholar : PubMed/NCBI
9	Liu L, Kou P, Zeng Q, Pei G, Li Y, Liang H, Xu G and Chen S: CD4+ T lymphocytes, especially Th2 cells, contribute to the progress of renal fibrosis. Am J Nephrol. 36:386–396. 2012. View Article : Google Scholar : PubMed/NCBI
10	Lech M, Gröbmayr R, Ryu M, Lorenz G, Hartter I, Mulay SR, Susanti HE, Kobayashi KS, Flavell RA and Anders HJ: Macrophage phenotype controls long-term AKI outcomes-kidney regeneration versus atrophy. J Am Soc Nephrol. 25:292–304. 2014. View Article : Google Scholar : PubMed/NCBI
11	Tao X, Yin L, Xu L and Peng J: Dioscin: A diverse acting natural compound with therapeutic potential in metabolic diseases, cancer, inflammation and infections. Pharmacol Res. 137:259–269. 2018. View Article : Google Scholar : PubMed/NCBI
12	Duan H, Zhang Q, Liu J, Li R, Wang D, Peng W and Wu C: Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis. Pharmacol Res. 168:1055992021. View Article : Google Scholar : PubMed/NCBI
13	Wang D and Wang X: Diosgenin and its analogs: Potential protective agents against atherosclerosis. Drug Des Devel Ther. 16:2305–2323. 2022. View Article : Google Scholar : PubMed/NCBI
14	Passos FRS, Araújo-Filho HG, Monteiro BS, Shanmugam S, Araújo AAS, Almeida JRGDS, Thangaraj P, Júnior LJQ and Quintans JSS: Anti-inflammatory and modulatory effects of steroidal saponins and sapogenins on cytokines: A review of pre-clinical research. Phytomedicine. 96:1538422022. View Article : Google Scholar : PubMed/NCBI
15	Gu L, Tao X, Xu Y, Han X, Qi Y, Xu L, Yin L and Peng J: Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway. Toxicol Appl Pharmacol. 292:19–29. 2016. View Article : Google Scholar : PubMed/NCBI
16	Yu H, Lin L, Zhang Z, Zhang H and Hu H: Targeting NF-κB pathway for the therapy of diseases: Mechanism and clinical study. Signal Transduct Target Ther. 5:2092020. View Article : Google Scholar : PubMed/NCBI
17	Qiao Y, Xu L, Tao X, Yin L, Qi Y, Xu Y, Han X, Tang Z, Ma X, Liu K and Peng J: Protective effects of dioscin against fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress, fibrosis, lipid metabolism and inflammation. Toxicol Lett. 284:37–45. 2018. View Article : Google Scholar : PubMed/NCBI
18	Cao D, Wang Y, Zhang Y, Zhang Y, Huang Q, Yin Z, Cai G, Chen X and Sun X: Regulation of connective tissue growth factor expression by miR-133b for the treatment of renal interstitial fibrosis in aged mice with unilateral ureteral obstruction. Stem Cell Res Ther. 12:1712021. View Article : Google Scholar : PubMed/NCBI
19	Gu L, Wang Y, Yang G, Tilyek A, Zhang C, Li S, Yu B, Chai C and Cao Z: Ribes diacanthum Pall (RDP) ameliorates UUO-induced renal fibrosis via both canonical and non-canonical TGF-β signaling pathways in mice. J Ethnopharmacol. 231:302–310. 2019. View Article : Google Scholar : PubMed/NCBI
20	Hosseinian S, Rad AK, Bideskan AE, Soukhtanloo M, Sadeghnia H, Shafei MN, Motejadded F, Mohebbati R, Shahraki S and Beheshti F: Thymoquinone ameliorates renal damage in unilateral ureteral obstruction in rats. Pharmacol Rep. 69:648–657. 2017. View Article : Google Scholar : PubMed/NCBI
21	El-Abhar H, Abd El Fattah MA, Wadie W and El-Tanbouly DM: Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington's disease. PLoS One. 13:e2038372018. View Article : Google Scholar
22	Liu S, Chen X, Zhang S, Wang X, Du X, Chen J and Zhou G: miR-106b-5p targeting SIX1 inhibits TGF-β1-induced pulmonary fibrosis and epithelial-mesenchymal transition in asthma through regulation of E2F1. Int J Mol Med. 47:048552021. View Article : Google Scholar
23	Okarmus J, Bogetofte H, Schmidt SI, Ryding M, García-López S, Ryan BJ, Martínez-Serrano A, Hyttel P and Meyer M: Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation. Sci Rep. 10:102782020. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Yamaguchi J, Tanaka T and Nangaku M: Recent advances in understanding of chronic kidney disease. F1000Res. 4:12122015. View Article : Google Scholar : PubMed/NCBI
26	Vernon MA, Mylonas KJ and Hughes J: Macrophages and renal fibrosis. Semin Nephrol. 30:302–317. 2010. View Article : Google Scholar : PubMed/NCBI
27	Wada T, Furuichi K, Sakai N, Iwata Y, Kitagawa K, Ishida Y, Kondo T, Hashimoto H, Ishiwata Y, Mukaida N, et al: Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol. 15:940–948. 2004. View Article : Google Scholar : PubMed/NCBI
28	Liao Y, Tan RZ, Li JC, Liu TT, Zhong X, Yan Y, Yang JK, Lin X, Fan JM and Wang L: Isoliquiritigenin attenuates UUO-induced renal inflammation and fibrosis by inhibiting mincle/Syk/NF-kappa B signaling pathway. Drug Des Devel Ther. 14:1455–1468. 2020. View Article : Google Scholar : PubMed/NCBI
29	Zhong Y, Liu J, Sun D, Guo T, Yao Y, Xia X, Shi C and Peng X: Dioscin relieves diabetic nephropathy via suppressing oxidative stress and apoptosis, and improving mitochondrial quality and quantity control. Food Funct. 13:3660–3673. 2022. View Article : Google Scholar : PubMed/NCBI
30	Cai S, Chen J and Li Y: Dioscin protects against diabetic nephropathy by inhibiting renal inflammation through TLR4/NF-κB pathway in mice. Immunobiology. 225:1519412020. View Article : Google Scholar : PubMed/NCBI
31	Zhang Y, Xu Y, Qi Y, Xu L, Song S, Yin L, Tao X, Zhen Y, Han X, Ma X, et al: Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation. Toxicology. 378:53–64. 2017. View Article : Google Scholar : PubMed/NCBI
32	Zhang Y, Tao X, Yin L, Xu L, Xu Y, Qi Y, Han X, Song S, Zhao Y, Lin Y, et al: Protective effects of dioscin against cisplatin-induced nephrotoxicity via the microRNA-34a/sirtuin 1 signalling pathway. Br J Pharmacol. 174:2512–2527. 2017. View Article : Google Scholar : PubMed/NCBI
33	Mankan AK, Lawless MW, Gray SG, Kelleher D and McManus R: NF-kappaB regulation: The nuclear response. J Cell Mol Med. 13:631–643. 2009. View Article : Google Scholar : PubMed/NCBI
34	Mitchell S, Vargas J and Hoffmann A: Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med. 8:227–241. 2016. View Article : Google Scholar : PubMed/NCBI
35	Hirano T: IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 33:127–148. 2021. View Article : Google Scholar : PubMed/NCBI
36	Zusso M, Lunardi V, Franceschini D, Pagetta A, Lo R, Stifani S, Frigo AC, Giusti P and Moro S: Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway. J Neuroinflammation. 16:1482019. View Article : Google Scholar : PubMed/NCBI
37	Kelley N, Jeltema D, Duan Y and He Y: The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci. 20:33282019. View Article : Google Scholar : PubMed/NCBI
38	Black LM, Lever JM and Agarwal A: Renal inflammation and fibrosis: A double-edged sword. J Histochem Cytochem. 67:663–681. 2019. View Article : Google Scholar : PubMed/NCBI
39	Bianconi V, Sahebkar A, Atkin SL and Pirro M: The regulation and importance of monocyte chemoattractant protein-1. Curr Opin Hematol. 25:44–51. 2018. View Article : Google Scholar : PubMed/NCBI
40	Du Y, Zhang H, Guo Y, Song K, Zeng L, Chen Y, Xie Z and Li R: CD38 deficiency up-regulated IL-1β and MCP-1 through TLR4/ERK/NF-κB pathway in sepsis pulmonary injury. Microbes Infect. 23:1048452021. View Article : Google Scholar : PubMed/NCBI
41	Afonina IS, Zhong Z, Karin M and Beyaert R: Limiting inflammation-the negative regulation of NF-κB and the NLRP3 inflammasome. Nat Immunol. 18:861–869. 2017. View Article : Google Scholar : PubMed/NCBI
42	Zhang WJ, Chen SJ, Zhou SC, Wu SZ and Wang H: Inflammasomes and fibrosis. Front Immunol. 12:6431492021. View Article : Google Scholar : PubMed/NCBI
43	Otto G: IL-1β switches on kidney fibrosis. Nat Rev Nephrol. 14:4752018. View Article : Google Scholar : PubMed/NCBI
44	Klinkhammer BM, Floege J and Boor P: PDGF in organ fibrosis. Mol Aspects Med. 62:44–62. 2018. View Article : Google Scholar : PubMed/NCBI
45	Hayashi N, Yoshimoto T, Izuhara K, Matsui K, Tanaka T and Nakanishi K: T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-gamma and IL-13 production. Proc Natl Acad Sci USA. 104:14765–14770. 2007. View Article : Google Scholar : PubMed/NCBI
46	Liang H, Xu F, Zhang T, Huang J, Guan Q, Wang H and Huang Q: Inhibition of IL-18 reduces renal fibrosis after ischemia-reperfusion. Biomed Pharmacother. 106:879–889. 2018. View Article : Google Scholar : PubMed/NCBI
47	Zhao W, Ma L, Cai C and Gong X: Caffeine inhibits NLRP3 inflammasome activation by suppressing MAPK/NF-κB and A2aR signaling in LPS-induced THP-1 macrophages. Int J Biol Sci. 15:1571–1581. 2019. View Article : Google Scholar : PubMed/NCBI
48	Wen Y, Lu X, Ren J, Privratsky JR, Yang B, Rudemiller NP, Zhang J, Griffiths R, Jain MK, Nedospasov SA, et al: KLF4 in macrophages attenuates TNFα-mediated kidney injury and fibrosis. J Am Soc Nephrol. 30:1925–1938. 2019. View Article : Google Scholar : PubMed/NCBI
49	Zhang L, Xie J, Gan R, Wu Z, Luo H, Chen X, Lu Y, Wu L and Zheng D: Synergistic inhibition of lung cancer cells by EGCG and NF-κB inhibitor BAY11-7082. J Cancer. 10:6543–6556. 2019. View Article : Google Scholar : PubMed/NCBI