The Effect of N-Acetylcysteine Use on Endoplasmic Reticulum Stress in the Kidney Tissues of Obese Rats

Year 2023, Volume: 16 Issue: 3, 301 - 309, 30.09.2023

Musa Tatar

https://doi.org/10.30607/kvj.1312847

Abstract

Endoplasmic reticulum (ER) stress has recently acquired increasing importance in the pathogenesis of obesity-associated kidney disease. N-acetylcysteine, otherwise known as NAC, is an antioxidant that works directly and indirectly by increasing the production of antioxidants in cells. A diet consisting of 60% calories from fat was used to establish the obesity model for the present investigation. In the NAC and obesity + NAC (ObNAC) groups, NAC was administered by intragastric tube at 150 mg/kg for eight weeks. GRP78 and PERK expressions were determined immunohistochemically in sections collected from kidney tissues at the end of the experiment. The GRP78 H score was significantly higher in the obese group than in the control, NAC, and ObNAC groups (p<0.01). The ObNAC group H-score was significantly lower than that of the obese group (p < 0.01) but was not different from the control and NAC groups. The obese group PERK H-score was also significantly higher than the control, NAC, and ObNAC groups (p<0.01). In the ObNAC group, the H-score was significantly lower than that in the obese group (p<0.01) and significantly higher than those in the control and NAC groups (p<0.01). Increasing changes in stress markers may be improved by NAC application, since obesity induced by a high-fat diet activates ER stress in kidney tissue.

Keywords

ER stress, GRP78, N-acetylcysteine, Obesity, PERK

Obez Sıçanların Böbrek Dokularında N-Asetilsistein Kullanımının Endoplazmik Retikulum Stresi Üzerine Etkisi

Abstract

Endoplazmik retikulum (ER) stresi son zamanlarda obezite ile ilişkili böbrek hastalığının patogenezinde artan bir önem kazanmıştır. N-asetilsistein (NAC), hücrelerde antioksidan üretimini artırarak doğrudan ve dolaylı olarak çalışan bir antioksidandır. Çalışmada, kalorinin %60’ını yağdan elde eden bir diyet ile obezite modeli oluşturuldu. NAC ve obezite + NAC (ObNAC) gruplarında NAC intragastrik tüp ile 150 mg/kg dozunda sekiz hafta süreyle uygulandı. Deney sonunda elde edilen böbrek dokularından alınan kesitlerde GRP78 ve PERK ekspresyonları immünohistokimyasal olarak belirlendi. GRP78'in H skoru obez grubunda kontrol, NAC ve ObNAC gruplarına göre anlamlı olarak yüksekti (p<0.01). ObNAC grubundaki H skoru, obez grubundan önemli ölçüde düşüktü (p < 0.01). Ayrıca bu grubun skoru kontrol ve NAC gruplarıyla benzerdi. Obez grubunda PERK H skoru kontrol, NAC ve ObNAC gruplarına göre anlamlı olarak yüksekti (p<0.01). ObNAC grubunda H skoru obez grubuna göre anlamlı olarak düşük (p<0.01), kontrol ve NAC gruplarına göre anlamlı olarak yüksekti (p<0.01). Yüksek yağlı diyet ile oluşan obezite böbrek dokusunda ER stresine neden olduğundan stres belirteçlerinde artan değişikliklerin NAC uygulaması ile iyileştirilebileceği düşünülebilir.

Keywords

ER stres, GRP78, N-asetilsistein, Obezite, PERK

References

• Adams, C. J., Kopp, M. C., Larburu, N., Nowak, P. R., & Ali, M. M. U. (2019). Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1. Frontiers in Molecular Biosciences, 6. https://doi.org/10.3389/fmolb.2019.00011
• Ajoolabady, A., Liu, S., Klionsky, D. J., Lip, G. Y. H., Tuomilehto, J., Kavalakatt, S., Pereira, D. M., Samali, A., & Ren, J. (2022). ER stress in obesity pathogenesis and management. Trends in Pharmacological Sciences, 43(2), 97–109. https://doi.org/10.1016/j.tips.2021.11.011
• Ajoolabady, A., Wang, S., Kroemer, G., Klionsky, D. J., Uversky, V. N., Sowers, J. R., Aslkhodapasandhokmabad, H., Bi, Y., Ge, J., & Ren, J. (2021). ER Stress in Cardiometabolic Diseases: From Molecular Mechanisms to Therapeutics. Endocrine Reviews, 42(6), 839–871. https://doi.org/10.1210/endrev/bnab006
• Almanza, A., Carlesso, A., Chintha, C., Creedican, S., Doultsinos, D., Leuzzi, B., Luís, A., McCarthy, N., Montibeller, L., More, S., Papaioannou, A., Püschel, F., Sassano, M. L., Skoko, J., Agostinis, P., de Belleroche, J., Eriksson, L. A., Fulda, S., Gorman, A. M., & Samali, A. (2019). Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. The FEBS Journal, 286(2), 241–278. https://doi.org/10.1111/febs.14608
• Angelidi, A. M., Belanger, M. J., Kokkinos, A., Koliaki, C. C., & Mantzoros, C. S. (2022). Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy. Endocrine Reviews, 43(3), 507–557. https://doi.org/10.1210/endrev/bnab034
• Bhattarai, K. R., Riaz, T. A., Kim, H.-R., & Chae, H. J. (2021). The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling. Experimental & Molecular Medicine, 53(2), 151–167. https://doi.org/10.1038/s12276-021-00560-8
• Burgos-Morón, E., Abad-Jiménez, Z., Martinez de Maranon, A., Iannantuoni, F., Escribano-López, I., López-Domènech, S., & Víctor, V. M. (2019). Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues. Journal of Clinical Medicine, 8(9), 1385. https://doi.org/10.3390/jcm8091385
• Chen, J., Guo, Y., Zeng, W., Huang, L., Pang, Q., Nie, L., Mu, J., Yuan, F., & Feng, B. (2014). ER stress triggers MCP-1 expression through SET7/9-induced histone methylation in the kidneys of db/db mice. American Journal of Physiology-Renal Physiology, 306(8), F916–F925. https://doi.org/10.1152/ajprenal.00697.2012
• Chen, Y., Wu, Z., Zhao, S., & Xiang, R. (2016). Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity. Scientific Reports, 6(1), 27486. https://doi.org/10.1038/srep27486
• Cherngwelling, R., Pengrattanachot, N., Swe, M. T., Thongnak, L., Promsan, S., Phengpol, N., Sutthasupha, P., & Lungkaphin, A. (2021). Agomelatine protects against obesity-induced renal injury by inhibiting endoplasmic reticulum stress/apoptosis pathway in rats. Toxicology and Applied Pharmacology, 425, 115601. https://doi.org/10.1016/j.taap.2021.115601
• Chong, W., Shastri, M., & Eri, R. (2017). Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Nexus Implicated in Bowel Disease Pathophysiology. International Journal of Molecular Sciences, 18(4), 771. https://doi.org/10.3390/ijms18040771
• Cui, X., Zhang, Y., Lu, Y., & Xiang, M. (2022). ROS and Endoplasmic Reticulum Stress in Pulmonary Disease. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.879204
• Dean, O., Giorlando, F., & Berk, M. (2011). N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. Journal of Psychiatry & Neuroscience, 36(2), 78–86. https://doi.org/10.1503/jpn.100057
• Dludla, P. V., Mazibuko-Mbeje, S. E., Nyambuya, T. M., Mxinwa, V., Tiano, L., Marcheggiani, F., Cirilli, I., Louw, J., & Nkambule, B. B. (2019). The beneficial effects of N-acetyl cysteine (NAC) against obesity associated complications: A systematic review of pre-clinical studies. Pharmacological Research, 146, 104332. https://doi.org/10.1016/j.phrs.2019.104332
• Elbini Dhouib, I., Jallouli, M., Annabi, A., Gharbi, N., Elfazaa, S., & Lasram, M. M. (2016). A minireview on N -acetylcysteine: An old drug with new approaches. Life Sciences, 151, 359–363. https://doi.org/10.1016/j.lfs.2016.03.003
• Gu, Y., Huang, F., Wang, Y., Chen, C., Wu, S., Zhou, S., Hei, Z., & Yuan, D. (2018). Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury. Journal of Translational Medicine, 16(1), 117. https://doi.org/10.1186/s12967-018-1493-8
• Hetz, C., & Papa, F. R. (2018). The unfolded protein response and cell fate control. Molecular cell, 69(2), 169-181. https://doi.org/10.1016/j.molcel.2017.06.017
• Ho, E., Chen, G., & Bray, T. M. (1999). Supplementation of N‐acetylcysteine inhibits NFκB activation and protects against alloxan‐induced diabetes in CD‐1 mice. The FASEB journal, 13(13), 1845-1854. https://doi.org/10.1096/fasebj.13.13.1845
• Hu, Y., Wang, Y., Yan, T., Feng, D., Ba, Y., Zhang, H., Zhu, J., Cheng, X., Cui, L., & Huang, H. (2019). N-acetylcysteine alleviates fluoride-induced testicular apoptosis by modulating IRE1α/JNK signaling and nuclear Nrf2 activation. Reproductive Toxicology, 84, 98–107. https://doi.org/10.1016/j.reprotox.2019.01.001
• Kawasaki, N., Asada, R., Saito, A., Kanemoto, S., & Imaizumi, K. (2012). Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Scientific Reports, 2(1), 799. https://doi.org/10.1038/srep00799
• Kim, G. W., Lin, J. E., Blomain, E. S., & Waldman, S. A. (2013). Antiobesity Pharmacotherapy: New Drugs and Emerging Targets. Clinical Pharmacology & Therapeutics, 95(1), 53–66. https://doi.org/10.1038/clpt.2013.204
• La Russa, D., Giordano, F., Marrone, A., Parafati, M., Janda, E., & Pellegrino, D. (2019). Oxidative Imbalance and Kidney Damage in Cafeteria Diet-Induced Rat Model of Metabolic Syndrome: Effect of Bergamot Polyphenolic Fraction. Antioxidants, 8(3), 66. https://doi.org/10.3390/antiox8030066
• Lee, E. S., Kim, H. M., Kang, J. S., Lee, E. Y., Yadav, D., Kwon, M.-H., Kim, Y. M., Kim, H. S., & Chung, C. H. (2016). Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model. Nephrology Dialysis Transplantation, 31(3), 391–400. https://doi.org/10.1093/ndt/gfv377
• Lee, J., & Ozcan, U. (2014). Unfolded Protein Response Signaling and Metabolic Diseases. Journal of Biological Chemistry, 289(3), 1203–1211. https://doi.org/10.1074/jbc.R113.534743
• Li, B., Leung, J. C. K., Chan, L. Y. Y., Yiu, W. H., Li, Y., Lok, S. W. Y., Liu, W. H., Chan, K. W., Tse, H. F., Lai, K. N., & Tang, S. C. W. (2019). Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells via Hepatocyte Growth Factor/c-Met Signaling in Obesity-Associated Kidney Injury. Stem Cells Translational Medicine, 8(9), 898–910. https://doi.org/10.1002/sctm.18-0265
• Lin, T., Lee, J., Kang, J., Shin, H., Lee, J., & Jin, D. (2019). Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response (UPR) in Mammalian Oocyte Maturation and Preimplantation Embryo Development. International Journal of Molecular Sciences, 20(2), 409. https://doi.org/10.3390/ijms20020409
• Liñares-Pose, L., Rial-Pensado, E., Estévez-Salguero, Á., Milbank, E., González-García, I., Rodríguez, C., Seoane-Collazo, P., Martinez-Sánchez, N., Nogueiras, R., Prieto, D., Diéguez, C., Contreras, C., & López, M. (2018). Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake. Genes, 9(7), 357. https://doi.org/10.3390/genes9070357
• Liu, G., Sun, Y., Li, Z., Song, T., Wang, H., Zhang, Y., & Ge, Z. (2008). Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease. Biochemical and biophysical research communications, 370(4), 651-656. https://doi.org/10.1016/j.bbrc.2008.04.031
• Lu, Y., Zhang, Y., Lou, Y., Cui, W., & Miao, L. (2020). Sulforaphane suppresses obesity-related glomerulopathy-induced damage by enhancing autophagy via Nrf2. Life Sciences, 258, 118153. https://doi.org/10.1016/j.lfs.2020.118153
• Masenga, S. K., Kabwe, L. S., Chakulya, M., & Kirabo, A. (2023). Mechanisms of Oxidative Stress in Metabolic Syndrome. International Journal of Molecular Sciences, 24(9), 7898. https://doi.org/10.3390/ijms24097898
• Munusamy, S., do Carmo, J. M., Hosler, J. P., & Hall, J. E. (2015). Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin. American Journal of Physiology-Renal Physiology, 309(8), F731–F743. https://doi.org/10.1152/ajprenal.00188.2015
• Pengrattanachot, N., Cherngwelling, R., Jaikumkao, K., Pongchaidecha, A., Thongnak, L., Swe, M. T., Chatsudthipong, V., & Lungkaphin, A. (2020). Atorvastatin attenuates obese-induced kidney injury and impaired renal organic anion transporter 3 function through inhibition of oxidative stress and inflammation. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1866(6), 165741. https://doi.org/10.1016/j.bbadis.2020.165741
• Promsan, S., Thongnak, L., Pengrattanachot, N., Phengpol, N., Sutthasupha, P., & Lungkaphin, A. (2022). Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats. Food and Chemical Toxicology, 165, 113190. https://doi.org/10.1016/j.fct.2022.113190
• Samuni, Y., Goldstein, S., Dean, O. M., & Berk, M. (2013). The chemistry and biological activities of N-acetylcysteine. Biochimica et Biophysica Acta (BBA) - General Subjects, 1830(8), 4117–4129. https://doi.org/10.1016/j.bbagen.2013.04.016
• Santos, P., Herrmann, A. P., Benvenutti, R., Noetzold, G., Giongo, F., Gama, C. S., Piato, A. L., & Elisabetsky, E. (2017). Anxiolytic properties of N -acetylcysteine in mice. Behavioural Brain Research, 317, 461–469. https://doi.org/10.1016/j.bbr.2016.10.010
• Sarvani, C., Sireesh, D., & Ramkumar, K. M. (2017). Unraveling the role of ER stress inhibitors in the context of metabolic diseases. Pharmacological Research, 119, 412–421. https://doi.org/10.1016/j.phrs.2017.02.018
• Schwarz, D. S., & Blower, M. D. (2016). The endoplasmic reticulum: structure, function and response to cellular signaling. Cellular and molecular life sciences, 73, 79-94. https://doi.org/10.1007/s00018-015-2052-6
• Sun, Y., Pu, L. Y., Lu, L., Wang, X.-H., Zhang, F., & Rao, J. H. (2014). N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia-reperfusion injury. World Journal of Gastroenterology, 20(41), 15289–15298. https://doi.org/10.3748/wjg.v20.i41.15289
• Tanaka, Y., Gleason, C. E., Tran, P. O. T., Harmon, J. S., & Robertson, R. P. (1999). Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proceedings of the National Academy of Sciences, 96(19), 10857-10862. https://doi.org/10.1073/pnas.96.19.10857
• Tatar, M., Tufekci, K. K., Uslu, S., & Öner, J. (2023). Expression of ADAMTS 1-4-8 and placental growth factor in ovary and oviduct during pregnancy in the first trimester. Anatomia, Histologia, Embryologia. 52, 619– 626. https://doi.org/10.1111/ahe.12922
• Tsai, C. C., Chen, Y. J., Yu, H. R., Huang, L. T., Tain, Y. L., Lin, I. C., Sheen, J. M., Wang, P. W., & Tiao, M. M. (2020). Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice. Lipids in Health and Disease, 19(1), 105. https://doi.org/10.1186/s12944-020-01274-y
• Tüfekci, K. K., Bakirhan, E. G., & Terzi, F. (2023). A Maternal High-Fat Diet Causes Anxiety-Related Behaviors by Altering Neuropeptide Y1 Receptor and Hippocampal Volumes in Rat Offspring: the Potential Effect of N-Acetylcysteine. Molecular Neurobiology, 60(3), 1499–1514. https://doi.org/10.1007/s12035-022-03158-x
• Tümer, N. B. (2020). N-acetyl cysteine attenuates ferroptosis mediated lung injury induced by lower limb ischaemia/reperfusion. Turkish Journal of Clinics and Laboratory, 11(4), 288–293. https://doi.org/10.18663/tjcl.769961
• Wang, C., Wu, M., Arvapalli, R., Dai, X., Mahmood, M., Driscoll, H., Rice, K. M., & Blough, E. (2014). Acetaminophen Attenuates Obesity-Related Renal Injury Through ER-Mediated Stress Mechanisms. Cellular Physiology and Biochemistry, 33(4), 1139–1148. https://doi.org/10.1159/000358683
• Xu, T., Sheng, Z., & Yao, L. (2017). Obesity-related glomerulopathy: pathogenesis, pathologic, clinical characteristics and treatment. Frontiers of Medicine, 11(3), 340–348. https://doi.org/10.1007/s11684-017-0570-3
• Zafarullah, M., Li, W. Q., Sylvester, J., & Ahmad, M. (2003). Molecular mechanisms of N -acetylcysteine actions. Cellular and Molecular Life Sciences (CMLS), 60(1), 6–20. https://doi.org/10.1007/s000180300001
• Zeeshan, H., Lee, G., Kim, H. R., & Chae, H. J. (2016). Endoplasmic Reticulum Stress and Associated ROS. International Journal of Molecular Sciences, 17(3), 327. https://doi.org/10.3390/ijms17030327
• Zhang, L., Zhu, Z., Liu, J., Zhu, Z., & Hu, Z. (2014). Protective effect of N-acetylcysteine (NAC) on renal ischemia/reperfusion injury through Nrf2 signaling pathway. Journal of Receptors and Signal Transduction, 34(5), 396–400. https://doi.org/10.3109/10799893.2014.908916
• Zhao, S., Liu, Y., Wang, F., Xu, D., & Xie, P. (2018). N-acetylcysteine protects against microcystin-LR-induced endoplasmic reticulum stress and germ cell apoptosis in zebrafish testes. Chemosphere, 204, 463–473. https://doi.org/10.1016/j.chemosphere.2018.04.020