灵芝多糖通过增加Nrf2、降低IL-1阻止糖尿病肾病的铁死亡
Ganoderma lucidum Polysaccharide Prevented Ferroptosis in Diabetes Nephropathy by Inhibiting IL-1 and Enhancing Nrf2
DOI: 10.12677/ACM.2023.13102228, PDF,    科研立项经费支持
作者: 徐顺娟：青岛大学附属医院全科医学科，山东 青岛；青岛市黄岛区灵山卫中心卫生院内科，山东 青岛；万 磊：潍坊医学院附属医院内分泌科，山东 潍坊；张杰涛*：青岛大学附属医院全科医学科，山东 青岛
关键词: 糖尿病肾病；铁死亡；灵芝多糖；核红细胞2相关因子2；活性氧；Diabetes Nephropathy； Ferroptosis； Ganoderma lucidum Polysaccharide； Erythrocyte 2 Related Fac-tor 2； Reactive Oxygen Species
摘要: 目的：铁死亡导致多种急性、慢性肾损伤，包括糖尿病肾病(DN)，本研究评估灵芝多糖(GLPs)在抑制铁死亡，保护糖尿病诱导肾小管损伤的作用和机制。方法：调取GEO数据库数据，采用GSEA和加权基因共表达网络分析研究DN和铁死亡的关系。免疫浸润分析DN发病与炎症细胞和炎症因子之间的关系。高糖刺激的近端小管上皮细胞损伤和STZ诱导的糖尿病小鼠模型分别用于体外和体内实验。检测Nrf2表达、细胞活力、谷胱甘肽浓度和脂质过氧化，Elisa检测细胞IL-1的水平。结果：GLPs缓解高糖刺激的近端小管上皮细胞损伤，降低细胞MDA、ROS的水平，增加细胞表达Nrf2。GLPs的肾小管的保护作用能被Nrf2的抑制剂阻断。体内实验结果显示，GLPs能够降低小鼠血BNU、Cr，增加肾脏谷胱甘肽浓度。结论：GLPs能够通过增加Nrf2表达发挥抗氧化作用，抑制铁死亡，保护糖尿病所致的肾小管细胞死亡。
Abstract: Objective: Ferroptosis contributes to many kinds of acute and chronic renal injuries, including DN (diabetic nephropathy). This study evaluated the role and mechanism of Ganoderma lucidum poly-saccharides (GLPs) in inhibiting ferroptosis and protecting renal tubular injury induced by diabe-tes. Methods: Datasets from GEO cohort were collected, and relationship between DN and ferropto-sis was analyzed by GSEA analysis. Immune infiltration analysis was performed to investigate the relationship between DN pathogenesis and cytokines. High glucose-stimulated proximal tubular epithelial cell injury and diabetes mouse models were used in vitro and in vivo, respectively. GLPS was used to treat cells or mouse models. The expression of Nrf2, cell viability, glutathione concen-tration and lipid peroxidation, and the level of cellular inflammatory factors were detected. Results: GLPS could alleviate the injury of proximal tubular epithelial cells stimulated by high glucose, re-duce the level of intracellular MDA and ROS, and increase the expression of Nrf2 in cells. The pro-tective effect of GLPs on renal tubules can be blocked by the inhibitor of Nrf2. In vivo experiment results showed that GLPs could reduce the blood BNU and Cr, and increase the kidney glutathione concentration in mice. Conclusion: GLPs can play an antioxidant role by increasing the expression of Nrf2, inhibit ferroptosis, and protect renal tubular cell death caused by diabetes.
文章引用：徐顺娟, 万磊, 张杰涛. 灵芝多糖通过增加Nrf2、降低IL-1阻止糖尿病肾病的铁死亡[J]. 临床医学进展, 2023, 13(10): 15941-15951. https://doi.org/10.12677/ACM.2023.13102228

参考文献

[1] Zhang, L., Long, J., Jiang, W., Shi, Y., He, X., Zhou, Z., Li, Y., et al. (2016) Trends in Chronic Kidney Disease in Chi-na. The New England Journal of Medicine, 375, 905-906. [Google Scholar] [CrossRef] 
[2] Al Mamun, A., Ara Mimi, A., Wu, Y., Zaeem, M., Abdul Aziz, M., Aktar Suchi, S., Alyafeai, E., Munir, F. and Xiao, J. (2021) Py-roptosis in Diabetic Nephropathy. Clinica Chimica Acta, 523, 131-143. [Google Scholar] [CrossRef] [PubMed]
[3] Bayir, H., Anthonymuthu, T.S., Tyurina, Y.Y., Patel, S.J., Amoscato, A.A., Lamade, A.M., et al. (2020) Achieving Life through Death: Redox Biology of Lipid Peroxidation in Ferroptosis. Cell Chemical Biology, 27, 387-408. [Google Scholar] [CrossRef] [PubMed]
[4] Yang, W.S. and Stockwell, B.R. (2016) Ferroptosis: Death by Lipid Peroxidation. Trends in Cell Biology, 26, 165-176. [Google Scholar] [CrossRef] [PubMed]
[5] Friedmann Angeli, J.P., Schneider, M., Proneth, B., Tyurina, Y.Y., Tyurin, V.A., Hammond, V.J., et al. (2014) Inactivation of the Ferroptosis Regulator Gpx4 Triggers Acute Renal Failure in Mice. Nature Cell Biology, 16, 1180-1191. [Google Scholar] [CrossRef] [PubMed]
[6] Zhou, Y., Zhang, J., Guan, Q., Tao, X., Wang, J. and Li, W. (2022) The Role of Ferroptosis in the Development of Acute and Chronic Kidney Diseases. Journal of Cellular Physiology, 237, 4412-4427. [Google Scholar] [CrossRef] [PubMed]
[7] Martin-Sanchez, D., Ruiz-Andres, O., Poveda, J., Carrasco, S., Canna-ta-Ortiz, P., Sanchez-Nino, M.D., et al. (2017) Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Ac-id-Induced AKI. Journal of the American Society of Nephrology, 28, 218-229. [Google Scholar] [CrossRef] 
[8] Wang, W.J., Jiang, X., Gao, C.C. and Chen, Z.W. (2021) Salusin-beta Participates in High Glucoseinduced HK2 Cell Ferroptosis in a Nrf2 Dependent Manner. Molecular Medicine Re-ports, 24, Article No. 674. [Google Scholar] [CrossRef] [PubMed]
[9] Li, S., Zheng, L., Zhang, J., Liu, X. and Wu, Z. (2021) Inhibition of Ferroptosis by Up-Regulating Nrf2 Delayed the Progression of Diabetic Nephropathy. Free Radical Biology and Medi-cine, 162, 435-449. [Google Scholar] [CrossRef] [PubMed]
[10] Liu, X.J., Hu, X.K., Yang, H., Gui, L.M., Cai, Z.X., Qi, M.S. and Dai, C.M. (2022) A Review of Traditional Chinese Medicine on Treatment of Diabetic Nephropathy and the Involved Mechanisms. The American Journal of Chinese Medicine, 50, 1739-1779. [Google Scholar] [CrossRef] 
[11] Huang, W.J., Liu, W.J., Xiao, Y.H., Zheng, H.J., Xiao, Y., Jia, Q., et al. (2020) Tripterygium and Its Extracts for Diabetic Nephropathy: Efficacy and Pharmacological Mechanisms. Biomedicine & Pharmacotherapy, 121, Article ID: 109599. [Google Scholar] [CrossRef] [PubMed]
[12] Huang, D., Shen, P., Wang, C., Gao, J., Ye, C. and Wu, F. (2022) Calycosin Plays a Protective Role in Diabetic Kidney Disease through the Regulation of Ferroptosis. Pharmaceu-tical Biology, 60, 990-996. [Google Scholar] [CrossRef] [PubMed]
[13] Li, Y., Liang, W., Han, Y., Zhao, W., Wang, S. and Qin, C. (2022) Triterpenoids and Polysaccharides from Ganoderma lucidum Improve the Histomorphology and Function of Testes in Middle-Aged Male Mice by Alleviating Oxidative Stress and Cellular Apoptosis. Nutrients, 14, Article No. 4733. [Google Scholar] [CrossRef] [PubMed]
[14] Xu, J., Xiao, C., Xu, H., Yang, S., Chen, Z., Wang, H., et al. (2021) Anti-Inflammatory Effects of Ganoderma lucidum Sterols via Attenuation of the p38 MAPK and NF-kappaB Pathways in LPS-Induced RAW 264.7 Macrophages. Food and Chemical Toxicology, 150, Article ID: 112073. [Google Scholar] [CrossRef] [PubMed]
[15] Akhtar, M., Taha, N.M., Nauman, A., Mujeeb, I.B. and Al-Nabet, A. (2020) Diabetic Kidney Disease: Past and Present. Advances in Anatomic Pathology, 27, 87-97. [Google Scholar] [CrossRef] 
[16] Gorin, Y. and Block, K. (2013) Nox4 and Diabetic Nephropathy: With a Friend Like This, Who Needs Enemies? Free Radical Biology and Medicine, 61, 130-142. [Google Scholar] [CrossRef] [PubMed]
[17] Kim, S., Kang, S.W., Joo, J., Han, S.H., Shin, H., Nam, B.Y., et al. (2021) Correction: Characterization of Ferroptosis in Kidney Tubular Cell Death under Diabetic Conditions. Cell Death & Disease, 12, Article No. 382. [Google Scholar] [CrossRef] [PubMed]
[18] Wang, Y., Bi, R., Quan, F., Cao, Q., Lin, Y., Yue, C., et al. (2020) Ferroptosis Involves in Renal Tubular Cell Death in Diabetic Nephropathy. European Journal of Pharmacology, 888, Article ID: 173574. [Google Scholar] [CrossRef] [PubMed]
[19] Guo, M.F., Dai, Y.J., Gao, J.R. and Chen, P.J. (2020) Uncov-ering the Mechanism of Astragalus membranaceus in the Treatment of Diabetic Nephropathy Based on Network Phar-macology. Journal of Diabetes Research, 2020, Article ID: 5947304. [Google Scholar] [CrossRef] [PubMed]
[20] Barbosa, J.R., Oliveira, L.C., Almada-Vilhena, A.O., et al. (2020) Ob-taining Extracts Rich in Antioxidant Polysaccharides from the Edible Mushroom Pleurotus ostreatus Using Binary Sys-tem with Hot Water and Supercritical CO2. Food Chemistry, 330, Article ID: 127173. [Google Scholar] [CrossRef] [PubMed]
[21] Lu, J., He, R., Sun, P., Zhang, F., Linhardt, R.J. and Zhang, A. (2020) Molecular Mechanisms of Bioactive Polysaccharides from Ganoderma lucidum (Lingzhi), a Review. Interna-tional Journal of Biological Macromolecules, 150, 765-774. [Google Scholar] [CrossRef] [PubMed]
[22] Li, Y., Tang, J., Gao, H., Xu, Y., Han, Y., Shang, H., Lu, Y. and Qin, C. (2021) Ganoderma lucidum Triterpenoids and Polysaccharides Attenuate Atherosclerotic Plaque in High-Fat Diet Rabbits. Nutrition, Metabolism and Cardiovascular Diseases, 31, 1929-1938. [Google Scholar] [CrossRef] [PubMed]
[23] Wang, Y., Yan, S., Liu, X., Deng, F., Wang, P., Yang, L., et al. (2022) PRMT4 Promotes Ferroptosis to Aggravate Doxorubicin-Induced Cardiomyopathy via Inhibition of the Nrf2/GPX4 Pathway. Cell Death & Differentiation, 29, 1982-1995. [Google Scholar] [CrossRef] [PubMed]
[24] Dodson, M., Castro-Portuguez, R. and Zhang, D.D. (2019) NRF2 Plays a Critical Role in Mitigating Lipid Peroxidation and Ferroptosis. Redox Biology, 23, Article ID: 101107. [Google Scholar] [CrossRef] [PubMed]
[25] Martin-Sanchez, D., Poveda, J., Fontecha-Barriuso, M., Ruiz-Andres, O., Sanchez-Nino, M.D., Ruiz-Ortega, M., Ortiz, A. and Sanz, A.B. (2018) Targeting of Regulated Necro-sis in Kidney Disease. Nefrologia (Engl Ed), 38, 125-135. [Google Scholar] [CrossRef] [PubMed]
[26] Hu, X., Zhang, H., Zhang, Q., Yao, X., Ni, W. and Zhou, K. (2022) Emerging Role of STING Signalling in CNS Injury: Inflammation, Autophagy, Necroptosis, Ferroptosis and Py-roptosis. Journal of Neuroinflammation, 19, Article No. 242. [Google Scholar] [CrossRef] [PubMed]

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