Lycopene regulates the formation of calcium oxalate kidney stones by modulating reactive oxygen species(ROS) and NF-κB pathways.

El licopeno regula la formación de cálculos renales de oxalato cálcico modulando las vías de especies reactivas de oxígeno (ROS) y NF-κB.

• Liangwen Ye The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0003-9780-4688
• Yuhang Tang The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0009-6263-0570
• Zhijie Zhang The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0006-8535-0748
• Xiangyi Hou The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0004-5185-6965
• Wei Xu The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0004-0948-5822
• Xianghui Suo The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0008-1688-0694
• Li Zhang The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu province, China. https://orcid.org/0009-0002-2514-6690

DOI: https://doi.org/10.54817/IC.v66n2a07

Palabras clave: licopeno, células epiteliales tubulares renales, ácido oxálico, especies reactivas de oxígeno, apoptosis

Resumen

Este estudio tiene como objetivo determinar si el licopeno puede reducir el estrés oxidativo y el daño inflamatorio inducidos por la cristalización de oxalato de calcio en cultivos de células HK-2 a través de la modulación de especies reactivas de oxígeno (ROS) y las vías de señalización de NF-κB. Los cultivos celulares se dividieron en cuatro grupos: grupo control, grupo modelo (COM + ácido oxálico) y dos grupos de intervención con licopeno (COM + ácido oxálico + 5/10 μmol/L de licopeno). Después de 24 horas de cultivo, se determinaron la viabilidad, la LDH, los parámetros oxidativos y antioxidantes, el potencial de membrana mitocondrial, MCP-1, IL-6, la apoptosis y proteínas relacionadas, y la activación y expresión de NF-κB mediante métodos adecuados. En comparación con el grupo control, el grupo modelo mostró una actividad celular (p<0,001) y una capacidad antioxidante de GSH y SOD (p<0,05) disminuidas, junto con aumento significativo de LDH, MDA y la liberación de mediadores inflamatorios MCP-1 e IL-6 (p<0,05). Los niveles de expresión de proteínas para NF-κB, OPN, Bax, Cyt C y Caspasa-3 activa aumentaron (p<0,05), mientras que la expresión de la proteína Bcl-2 disminuyó significativamente (p<0,05). El potencial de membrana mitocondrial disminuyó. La intervención con licopeno redujo el daño celular (p<0,05), acompañada de una disminución de los niveles de LDH, MDA y los factores inflamatorios MCP-1 e IL-6 (p<0,05), y un aumento de la capacidad antioxidante de GSH y SOD (p<0,05). Se observó un aumento del potencial de membrana mitocondrial. No se observaron cambios significativos en la expresión de NF-κB. La expresión de OPN, Bax, Cyt C y Caspasa-3 disminuyó (p<0,05), mientras que la expresión de la proteína Bcl-2 aumentó. En conclusión, el licopeno disminuyó el daño celular al inhibir la peroxidación lipídica inducida por cristales de oxalato de calcio y oxalato, potenciar la actividad enzimática antioxidante intracelular, modular las vías inflamatorias de ROS y NF-κB, mejorar la integridad mitocondrial y ejercer efectos antiinflamatorios mediante la inhibición de la vía de señalización Bax/Caspasa-3 mediada por mitocondrias.

Citas

Tan S, Yuan D, Su H, Chen W, Zhu S, Yan B, et al. Prevalence of urolithiasis in China: a systematic review and meta-analysis. BJU Int. 2024;133:34-43. https://doi.org/10.1111/bju.16179.

Qin B, Wang Q, Lu Y, Li C, Hu H, Zhang J, et al. Losartan ameliorates calcium oxalate-induced elevation of stone-related proteins in renal tubular cells by inhibiting NADPH oxidase and oxidative stress. Oxid Med Cell Longev. 2018;2018:1271864. https://doi.org/10.1155/2018/1271864.

Kang J, Sun Y, Deng Y, Liu Q, Li D, Liu Y, et al. Autophagy-endoplasmic reticulum stress inhibition mechanism of superoxide dismutase in the formation of calcium oxalate kidney stones. Biomed Pharmacother. 2020;121:109649. https://doi.org/10.1016/j.biopha.2019.109649.

Khan SR. Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. J Urol. 2013;189:803-11. https://doi.org/10.1016/j.juro.2012.05.078.

Liu CB, Wang R, Yi YF, Gao Z, Chen YZ. Lycopene mitigates β-amyloid induced inflammatory response and inhibits NF-κB signaling at the choroid plexus in early stages of Alzheimer’s disease rats. J Nutr Biochem. 2018;53:66-71. https://doi.org/10.1016/j.jnutbio.2017.10.014.

Caseiro M AA, Costa A, Creagh-Flynn J, Johnson M, Simões S. Lycopene in human health. LWT. 2020;127. https://doi.org/10.1016/j.lwt.2020.109323.

Zhao Q, Yang F, Meng L, Chen D, Wang M, Lu X, et al. Lycopene attenuates chronic prostatitis/chronic pelvic pain syndrome by inhibiting oxidative stress and inflammation via the interaction of NF-κB, MAPKs, and Nrf2 signaling path-ways in rats. Andrology. 2020;8:747-755. https://doi.org/10.1111/andr.12747.

Sixing Y ZY. Reconsiderations of several key issues in the treatment of urolithiasis. Chinese J of Urol. 2018;9. https://doi.org/10.3760/cma.j.issn.1000-6702.2018.09.002.

Thongboonkerd V. Proteomics of crystal-cell interactions: a model for kidney stone research. Cells. 2019;8. https://doi.org/10.3390/cells8091076.

Liu Q, Liu Y, Guan X, Wu J, He Z, Kang J, et al. Effect of M2 macrophages on injury and apoptosis of renal tubular epithelial cells induced by calcium oxalate crystals. Kidney Blood Press Res. 2019;44:777-791. https://doi.org/10.1159/000501558.

Mulay SR, Kulkarni OP, Rupanagudi KV, Migliorini A, Darisipudi MN, Vilaysane A, et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL - 1β secretion. J Clin Invest. 2013;123:236- 246. https://doi.org/10.1172/jci63679.

Zabłocka A, Janusz M. [The two faces of reactive oxygen species]. Postepy Hig Med Dosw (Online). 2008;62:118-124.

Joshi S, Khan SR. Opportunities for future therapeutic interventions for hyperoxaluria: targeting oxidative stress. Expert Opin Ther Targets. 2019;23:379-391. https://doi.org/10.1080/14728222.2019.1599359.

Umekawa T, Tsuji H, Uemura H, Khan SR. Superoxide from NADPH oxidase as second messenger for the expression of osteopontin and monocyte chemoattractant protein-1 in renal epithelial cells exposed to calcium oxalate crystals. BJU Int. 2009;104:115-120. https://doi.org/10.1111/j.1464- 410X.2009.08374.x.

Patel M, Yarlagadda V, Adedoyin O, Saini V, Assimos DG, Holmes RP, et al. Oxalate induces mitochondrial dysfunction and disrupts redox homeostasis in a human monocyte derived cell line. Redox Biol. 2018;15:207-215. https://doi.org/10.1016/j.redox.2017.12.003.

Zuo L, Tozawa K, Okada A, Yasui T, Taguchi K, Ito Y, et al. A paracrine mechanism involving renal tubular cells, adipocytes and macrophages promotes kidney stone formation in a simulated metabolic syndrome environment. J Urol. 2014;191:1906-1912. https://doi.org/10.1016/j.juro.2014.01.013.

Boonla C, Hunapathed C, Bovornpadungkitti S, Poonpirome K, Tungsanga K, Sampatanukul P, et al. Messenger RNA expression of monocyte chemoattractant protein-1 and interleukin-6 in stone-containing kidneys. BJU Int. 2008;101:1170-1177. https://doi.org/10.1111/j.1464-410 X.2008.07461.x.

Khan SR, Joshi S, Wang W, Peck AB. Regulation of macromolecular modulators of urinary stone formation by reactive oxygen species: transcriptional study in an animal model of hyperoxaluria. Am J Physiol Renal Physiol. 2014;306:F1285-1295. https://doi.org/10.1152/ajprenal.00057.2014.

Lalier L, Vallette F, Manon S. Bcl-2 family members and the mitochondrial import machineries: The roads to death. Biomolecules. 2022;12. https://doi.org/10.3390/biom12020162.

Hu L, Chen M, Chen X, Zhao C, Fang Z, Wang H, et al. Chemotherapy induced pyroptosis is mediated by BAK/BAX-caspase 3-GSDME pathway and inhibited by 2-bro mopalmitate. Cell Death Dis. 2020;11:281. https://doi.org/10.1038/s41419-020-2476-2.

Khan SR. Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. Transl Androl Urol. 2014;3:256-276. https://doi.org/10.3978/j.issn.2223-4683.2014.06.04