Oxymatrine Attenuates High Glucose-induced NLRP3 Inflammasome-dependent Pyroptosis and Injury in Podocytes by Regulating SIRT1/NF-κB Pathway
Abstract
Diabetic nephropathy is a microvascular complication that leads to renal injury. Oxymatrine (OMT) is a matrine alkaloid and has been shown to ameliorate diabetic nephropathy. However, it is still unknown whether its mechanism involves podocytes, which play a critical role in diabetic nephropathy.
High glucose-induced podocytes (MPC5) were treated with OMT, the NOD-like receptor protein 3 (NLRP3) inhibitor MCC950, and the sirtuin 1 (SIRT1) inhibitor EX527. The effects on podocyte proliferation and apoptosis were assessed using cell counting kit-8 and flow cytometry. Immunofluorescence staining was performed to detect the expression of podocyte-associated proteins, NLRP3 inflammasome, and SIRT1. The levels of interleukin (IL)-1β and IL-18 were measured by enzyme-linked immunosorbent assay. Additionally, Western blot analysis was conducted to evaluate podocyte-related proteins, NLRP3 inflammasome-dependent pyroptosis-related proteins, and SIRT1/nuclear factor kappa B (NF-κB) pathway proteins, aiming to elucidate the mechanisms by which OMT improves podocyte injury.
OMT significantly promoted the proliferation of podocytes exposed to high glucose, inhibited their apoptosis, increased the levels of nephrin, Wilms tumor 1, podocin, and zonula occludens-1, and reduced pyroptosis-related proteins, IL-1β, and IL-18 (p < 0.05). It also increased SIRT1 and decreased the acetylation of NF-κB p65 (p < 0.05). The NLRP3 inhibitor MCC950 reduced podocyte pyroptosis under high glucose conditions, while the SIRT1 inhibitor EX527 reversed the protective effects of OMT on NLRP3 inflammasome-dependent pyroptosis and podocyte injury.
OMT ameliorates high glucose-induced podocyte injury by regulating the SIRT1/NF-κB pathway and inhibiting NLRP3 inflammasome-dependent pyroptosis.
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3. Feng J, Xie L, Yu X, Liu C, Dong H, Lu W, et al. Perilipin 5 ameliorates high-glucose-induced podocyte injury via Akt/GSK-3β/Nrf2-mediated suppression of apoptosis, oxidative stress, and inflammation. Biochem Biophys Res Commun. 2021;544:22-30.
4. Gan P, Ding L, Hang G, Xia Q, Huang Z,
Ye X, et al. Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson's Disease. Front Pharmacol. 2020;11:776.
5. Wang Y, Shou Z, Fan H, Xu M, Chen Q, Tang Q, et al. Protective effects of oxymatrine against DSS-induced acute intestinal inflammation in mice via blocking the RhoA/ROCK signaling pathway. Biosci Rep. 2019;39(7).
6. Xiao X, Hou X, Shi W, Hu C, Cui Y, Hu J, et al. Oxymatrine inhibits proliferation and apoptosis of human breast cancer cells through the regulation of miRNA-140-5P. Am J Transl Res. 2021;13(12):13674-82.
7. Sun Y, Xu L, Cai Q, Wang M, Wang X, Wang S, et al. Research progress on the pharmacological effects of matrine. Front Neurosci. 2022;16:977374.
8. Jin X, Fu W, Zhou J, Shuai N, Yang Y, Wang B. Oxymatrine attenuates oxidized low‑density lipoprotein‑induced HUVEC injury by inhibiting NLRP3 inflammasome‑mediated pyroptosis via the activation of the SIRT1/Nrf2 signaling pathway. Int J Mol Med. 2021;48(4).
9. Sun J, Wang S, Zhao Z, Lu J, Zhang Y, An W, et al. Oxymatrine Attenuates Ulcerative Colitis through Inhibiting Pyroptosis Mediated by the NLRP3 Inflammasome. Molecules. 2024;29(12).
10. Xiao Y, Peng C, Xiao Y, Liang D, Yuan Z, Li Z, et al. Oxymatrine Inhibits Twist-Mediated Renal Tubulointerstitial Fibrosis by Upregulating Id2 Expression. Front Physiol. 2020;11:599.
11. Xiao Y, Liang D, Li Z, Feng Z, Yuan Z, Zhang F, et al. BMP-7 Upregulates Id2 Through the MAPK Signaling Pathway to Improve Diabetic Tubulointerstitial Fibrosis and the Intervention of Oxymatrine. Front Pharmacol. 2022;13:900346.
12. Liu L, Wang Y, Yan R, Li S, Shi M, Xiao Y, et al. Oxymatrine Inhibits Renal Tubular EMT Induced by High Glucose via Upregulation of SnoN and Inhibition of TGF-β1/Smad Signaling Pathway. PLoS One. 2016;11(3):e0151986.
13. Jung SW, Moon JY. The role of inflammation in diabetic kidney disease. Korean J Intern Med. 2021;36(4):753-66.
14. Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch Pharm Res. 2021;44(1):16-35.
15. Qiu YY, Tang LQ. Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. Pharmacol Res. 2016;114:251-64.
16. Zhang B, Zhang X, Zhang C, Sun G, Sun X. Berberine Improves the Protective Effects of Metformin on Diabetic Nephropathy in db/db Mice through Trib1-dependent Inhibiting Inflammation. Pharm Res. 2021;38(11):1807-20.
17. Liu N, Xu L, Shi Y, Zhuang S. Podocyte Autophagy: A Potential Therapeutic Target to Prevent the Progression of Diabetic Nephropathy. J Diabetes Res. 2017;2017:3560238.
18. Li X, Zhang Y, Xing X, Li M, Liu Y, Xu A, et al. Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;168:115670.
19. Jiang L, Cui H, Ding J. Smad3 signalling affects high glucose-induced podocyte injury via regulation of the cytoskeletal protein transgelin. Nephrology (Carlton). 2020;25(9):659-66.
20. Itoh M, Nakadate K, Matsusaka T, Hunziker W, Sugimoto H. Effects of the differential expression of ZO-1 and ZO-2 on podocyte structure and function. Genes Cells. 2018;23(7):546-56.
21. Ettou S, Jung YL, Miyoshi T, Jain D, Hiratsuka
K, Schumacher V, et al. Epigenetic transcriptional reprogramming by WT1 mediates a repair
response during podocyte injury. Sci Adv. 2020;6(30):eabb5460.
22. Yan M, Li W, Wei R, Li S, Liu Y, Huang Y, et al. Identification of pyroptosis-related genes and potential drugs in diabetic nephropathy. J Transl Med. 2023;21(1):490.
23. Zhang K, Li M, Yin K, Wang M, Dong Q, Miao Z, et al. Hyperoside mediates protection from diabetes kidney disease by regulating ROS-ERK signaling pathway and pyroptosis. Phytother Res. 2023;37(12):5871-82.
24. Rao Z, Zhu Y, Yang P, Chen Z, Xia Y, Qiao C, et al. Pyroptosis in inflammatory diseases and cancer. Theranostics. 2022;12(9):4310-29.
25. Seoane PI, Lee B, Hoyle C, Yu S, Lopez-Castejon G, Lowe M, et al. The NLRP3-inflammasome as a sensor of organelle dysfunction. J Cell Biol. 2020;219(12).
26. Zhao C, Zhao W. NLRP3 Inflammasome-A Key Player in Antiviral Responses. Front Immunol. 2020;11:211.
27. Ge Q, Chen X, Zhao Y, Mu H, Zhang J. Modulatory mechanisms of NLRP3: Potential roles in inflammasome activation. Life Sci. 2021;267:118918.
28. Ma Q. Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction. Pharmacol Rev. 2023;75(3):487-520.
29. Shen Y, Xu Y, Shen P, Shen P, Bian Q, Han L, et al. A bifunctional fusion protein protected against diabetic nephropathy by suppressing NLRP3 activation. Appl Microbiol Biotechnol. 2023;107(7-8):2561-76.
30. Chen F, Wei G, Xu J, Ma X, Wang Q. Naringin ameliorates the high glucose-induced rat mesangial cell inflammatory reaction by modulating the NLRP3 Inflammasome. BMC Complement Altern Med. 2018;18(1):192.
31. Wang L, Hauenstein AV. The NLRP3 inflammasome: Mechanism of action, role in disease and therapies. Mol Aspects Med. 2020;76:100889.
32. Ram C, Gairola S, Verma S, Mugale MN, Bonam SR, Murty US, et al. Biochanin A Ameliorates Nephropathy in High-Fat Diet/Streptozotocin-Induced Diabetic Rats: Effects on NF-kB/NLRP3 Axis, Pyroptosis, and Fibrosis. Antioxidants (Basel). 2023;12(5).
33. Xu X, Qin Z, Zhang C, Mi X, Zhang C, Zhou F, et al. TRIM29 promotes podocyte pyroptosis in diabetic nephropathy through the NF-kB/NLRP3 inflammasome pathway. Cell Biol Int. 2023;47(6):1126-35.
34. Wang X, Fan L, Yin H, Zhou Y, Tang X, Fei X, et al. Protective effect of Aster tataricus extract on NLRP3-mediated pyroptosis of bladder urothelial cells. J Cell Mol Med. 2020;24(22):13336-45.
35. Burdette BE, Esparza AN, Zhu H, Wang S. Gasdermin D in pyroptosis. Acta Pharm Sin B. 2021;11(9):2768-82.
36. Lu F, Lan Z, Xin Z, He C, Guo Z, Xia X, et al. Emerging insights into molecular mechanisms underlying pyroptosis and functions of inflammasomes in diseases. J Cell Physiol. 2020;235(4):3207-21.
37. Fioranelli M, Roccia MG, Flavin D, Cota L. Regulation of Inflammatory Reaction in Health and Disease. Int J Mol Sci. 2021;22(10).
38. Rayego-Mateos S, Rodrigues-Diez RR, Fernandez-Fernandez B, Mora-Fernández C, Marchant V, Donate-Correa J, et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int. 2023;103(2):282-96.
39. Jiao F, Gong Z. The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases. Oxid Med Cell Longev. 2020;2020:6782872.
40. Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med (Berl). 2019;97(3):291-309.
41. Hong Q, Zhang L, Das B, Li Z, Liu B, Cai G, et al. Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int. 2018;93(6):1330-43.
42. Lassén E, Bouchareb R, Daehn IS. Podocyte as the link between sterile inflammation and diabetic kidney disease. Kidney Int. 2022;102(4):688-90.
43. Jayaraman S, Pazhani J, PriyaVeeraraghavan V, Raj AT, Somasundaram DB, Patil S. PCNA and Ki67: Prognostic proliferation markers for oral cancer. Oral oncology. 2022;130:105943.
44. Zhao K, Zhang H, Yang D. SIRT1 exerts protective effects by inhibiting endoplasmic reticulum stress and NF-κB signaling pathways. Front Cell Dev Biol. 2024;12:1405546.
45. Ghizzoni M, Haisma HJ, Maarsingh H, Dekker FJ. Histone acetyltransferases are crucial regulators in NF-κB mediated inflammation. Drug Discov Today. 2011;16(11-12):504-11.
46. Nadtochiy SM, Yao H, McBurney MW, Gu W, Guarente L, Rahman I, et al. SIRT1-mediated acute cardioprotection. Am J Physiol Heart Circ Physiol. 2011;301(4):H1506-12.
2. Jiang Z, Qian L, Yang R, Wu Y, Guo Y, Chen T. LncRNA TCF7 contributes to high glucose-induced damage in human podocytes by up-regulating SEMA3A via sponging miR-16-5p. J Diabetes Investig. 2023;14(2):193-204.
3. Feng J, Xie L, Yu X, Liu C, Dong H, Lu W, et al. Perilipin 5 ameliorates high-glucose-induced podocyte injury via Akt/GSK-3β/Nrf2-mediated suppression of apoptosis, oxidative stress, and inflammation. Biochem Biophys Res Commun. 2021;544:22-30.
4. Gan P, Ding L, Hang G, Xia Q, Huang Z,
Ye X, et al. Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson's Disease. Front Pharmacol. 2020;11:776.
5. Wang Y, Shou Z, Fan H, Xu M, Chen Q, Tang Q, et al. Protective effects of oxymatrine against DSS-induced acute intestinal inflammation in mice via blocking the RhoA/ROCK signaling pathway. Biosci Rep. 2019;39(7).
6. Xiao X, Hou X, Shi W, Hu C, Cui Y, Hu J, et al. Oxymatrine inhibits proliferation and apoptosis of human breast cancer cells through the regulation of miRNA-140-5P. Am J Transl Res. 2021;13(12):13674-82.
7. Sun Y, Xu L, Cai Q, Wang M, Wang X, Wang S, et al. Research progress on the pharmacological effects of matrine. Front Neurosci. 2022;16:977374.
8. Jin X, Fu W, Zhou J, Shuai N, Yang Y, Wang B. Oxymatrine attenuates oxidized low‑density lipoprotein‑induced HUVEC injury by inhibiting NLRP3 inflammasome‑mediated pyroptosis via the activation of the SIRT1/Nrf2 signaling pathway. Int J Mol Med. 2021;48(4).
9. Sun J, Wang S, Zhao Z, Lu J, Zhang Y, An W, et al. Oxymatrine Attenuates Ulcerative Colitis through Inhibiting Pyroptosis Mediated by the NLRP3 Inflammasome. Molecules. 2024;29(12).
10. Xiao Y, Peng C, Xiao Y, Liang D, Yuan Z, Li Z, et al. Oxymatrine Inhibits Twist-Mediated Renal Tubulointerstitial Fibrosis by Upregulating Id2 Expression. Front Physiol. 2020;11:599.
11. Xiao Y, Liang D, Li Z, Feng Z, Yuan Z, Zhang F, et al. BMP-7 Upregulates Id2 Through the MAPK Signaling Pathway to Improve Diabetic Tubulointerstitial Fibrosis and the Intervention of Oxymatrine. Front Pharmacol. 2022;13:900346.
12. Liu L, Wang Y, Yan R, Li S, Shi M, Xiao Y, et al. Oxymatrine Inhibits Renal Tubular EMT Induced by High Glucose via Upregulation of SnoN and Inhibition of TGF-β1/Smad Signaling Pathway. PLoS One. 2016;11(3):e0151986.
13. Jung SW, Moon JY. The role of inflammation in diabetic kidney disease. Korean J Intern Med. 2021;36(4):753-66.
14. Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch Pharm Res. 2021;44(1):16-35.
15. Qiu YY, Tang LQ. Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. Pharmacol Res. 2016;114:251-64.
16. Zhang B, Zhang X, Zhang C, Sun G, Sun X. Berberine Improves the Protective Effects of Metformin on Diabetic Nephropathy in db/db Mice through Trib1-dependent Inhibiting Inflammation. Pharm Res. 2021;38(11):1807-20.
17. Liu N, Xu L, Shi Y, Zhuang S. Podocyte Autophagy: A Potential Therapeutic Target to Prevent the Progression of Diabetic Nephropathy. J Diabetes Res. 2017;2017:3560238.
18. Li X, Zhang Y, Xing X, Li M, Liu Y, Xu A, et al. Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;168:115670.
19. Jiang L, Cui H, Ding J. Smad3 signalling affects high glucose-induced podocyte injury via regulation of the cytoskeletal protein transgelin. Nephrology (Carlton). 2020;25(9):659-66.
20. Itoh M, Nakadate K, Matsusaka T, Hunziker W, Sugimoto H. Effects of the differential expression of ZO-1 and ZO-2 on podocyte structure and function. Genes Cells. 2018;23(7):546-56.
21. Ettou S, Jung YL, Miyoshi T, Jain D, Hiratsuka
K, Schumacher V, et al. Epigenetic transcriptional reprogramming by WT1 mediates a repair
response during podocyte injury. Sci Adv. 2020;6(30):eabb5460.
22. Yan M, Li W, Wei R, Li S, Liu Y, Huang Y, et al. Identification of pyroptosis-related genes and potential drugs in diabetic nephropathy. J Transl Med. 2023;21(1):490.
23. Zhang K, Li M, Yin K, Wang M, Dong Q, Miao Z, et al. Hyperoside mediates protection from diabetes kidney disease by regulating ROS-ERK signaling pathway and pyroptosis. Phytother Res. 2023;37(12):5871-82.
24. Rao Z, Zhu Y, Yang P, Chen Z, Xia Y, Qiao C, et al. Pyroptosis in inflammatory diseases and cancer. Theranostics. 2022;12(9):4310-29.
25. Seoane PI, Lee B, Hoyle C, Yu S, Lopez-Castejon G, Lowe M, et al. The NLRP3-inflammasome as a sensor of organelle dysfunction. J Cell Biol. 2020;219(12).
26. Zhao C, Zhao W. NLRP3 Inflammasome-A Key Player in Antiviral Responses. Front Immunol. 2020;11:211.
27. Ge Q, Chen X, Zhao Y, Mu H, Zhang J. Modulatory mechanisms of NLRP3: Potential roles in inflammasome activation. Life Sci. 2021;267:118918.
28. Ma Q. Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction. Pharmacol Rev. 2023;75(3):487-520.
29. Shen Y, Xu Y, Shen P, Shen P, Bian Q, Han L, et al. A bifunctional fusion protein protected against diabetic nephropathy by suppressing NLRP3 activation. Appl Microbiol Biotechnol. 2023;107(7-8):2561-76.
30. Chen F, Wei G, Xu J, Ma X, Wang Q. Naringin ameliorates the high glucose-induced rat mesangial cell inflammatory reaction by modulating the NLRP3 Inflammasome. BMC Complement Altern Med. 2018;18(1):192.
31. Wang L, Hauenstein AV. The NLRP3 inflammasome: Mechanism of action, role in disease and therapies. Mol Aspects Med. 2020;76:100889.
32. Ram C, Gairola S, Verma S, Mugale MN, Bonam SR, Murty US, et al. Biochanin A Ameliorates Nephropathy in High-Fat Diet/Streptozotocin-Induced Diabetic Rats: Effects on NF-kB/NLRP3 Axis, Pyroptosis, and Fibrosis. Antioxidants (Basel). 2023;12(5).
33. Xu X, Qin Z, Zhang C, Mi X, Zhang C, Zhou F, et al. TRIM29 promotes podocyte pyroptosis in diabetic nephropathy through the NF-kB/NLRP3 inflammasome pathway. Cell Biol Int. 2023;47(6):1126-35.
34. Wang X, Fan L, Yin H, Zhou Y, Tang X, Fei X, et al. Protective effect of Aster tataricus extract on NLRP3-mediated pyroptosis of bladder urothelial cells. J Cell Mol Med. 2020;24(22):13336-45.
35. Burdette BE, Esparza AN, Zhu H, Wang S. Gasdermin D in pyroptosis. Acta Pharm Sin B. 2021;11(9):2768-82.
36. Lu F, Lan Z, Xin Z, He C, Guo Z, Xia X, et al. Emerging insights into molecular mechanisms underlying pyroptosis and functions of inflammasomes in diseases. J Cell Physiol. 2020;235(4):3207-21.
37. Fioranelli M, Roccia MG, Flavin D, Cota L. Regulation of Inflammatory Reaction in Health and Disease. Int J Mol Sci. 2021;22(10).
38. Rayego-Mateos S, Rodrigues-Diez RR, Fernandez-Fernandez B, Mora-Fernández C, Marchant V, Donate-Correa J, et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int. 2023;103(2):282-96.
39. Jiao F, Gong Z. The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases. Oxid Med Cell Longev. 2020;2020:6782872.
40. Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med (Berl). 2019;97(3):291-309.
41. Hong Q, Zhang L, Das B, Li Z, Liu B, Cai G, et al. Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int. 2018;93(6):1330-43.
42. Lassén E, Bouchareb R, Daehn IS. Podocyte as the link between sterile inflammation and diabetic kidney disease. Kidney Int. 2022;102(4):688-90.
43. Jayaraman S, Pazhani J, PriyaVeeraraghavan V, Raj AT, Somasundaram DB, Patil S. PCNA and Ki67: Prognostic proliferation markers for oral cancer. Oral oncology. 2022;130:105943.
44. Zhao K, Zhang H, Yang D. SIRT1 exerts protective effects by inhibiting endoplasmic reticulum stress and NF-κB signaling pathways. Front Cell Dev Biol. 2024;12:1405546.
45. Ghizzoni M, Haisma HJ, Maarsingh H, Dekker FJ. Histone acetyltransferases are crucial regulators in NF-κB mediated inflammation. Drug Discov Today. 2011;16(11-12):504-11.
46. Nadtochiy SM, Yao H, McBurney MW, Gu W, Guarente L, Rahman I, et al. SIRT1-mediated acute cardioprotection. Am J Physiol Heart Circ Physiol. 2011;301(4):H1506-12.
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| NOD-like receptor protein 3 inflammasome Oxymatrine Podocytes Pyroptosis SIRT1/NF-κB pathway | ||
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How to Cite
1.
Ouyang H, Chen D, Liu W. Oxymatrine Attenuates High Glucose-induced NLRP3 Inflammasome-dependent Pyroptosis and Injury in Podocytes by Regulating SIRT1/NF-κB Pathway. Iran J Allergy Asthma Immunol. 2024;:1-14.
