Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Melatonin Rescues Mesenchymal Stem Cells from Senescence Induced by the Uremic Toxin p-Cresol via Inhibiting mTOR-Dependent Autophagy

  • Yun, Seung Pil (Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine) ;
  • Han, Yong-Seok (Medical Science Research Institute, Soonchunhyang University Seoul Hospital) ;
  • Lee, Jun Hee (Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine) ;
  • Kim, Sang Min (Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine) ;
  • Lee, Sang Hun (Medical Science Research Institute, Soonchunhyang University Seoul Hospital)
  • Received : 2017.03.21
  • Accepted : 2017.04.26
  • Published : 2018.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

p-Cresol, found at high concentrations in the serum of chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body. p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether p-cresol induces senescence of mesenchymal stem cells, and whether melatonin can ameliorate abnormal autophagy response caused by p-cresol. We found that p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with melatonin prevented pro-senescence effects of p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway, melatonin enhanced catalase activity and thereby inhibited the accumulation of reactive oxygen species induced by p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with melatonin counteracted other pro-senescence changes caused by p-cresol, such as the increase in total 5'-AMP-activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of rapamycin. Ultimately, we discovered that melatonin restored the expression of senescence marker protein 30, which is normally suppressed because of the induction of the autophagy pathway in chronic kidney failure patients by p-cresol. Our findings suggest that stem cell senescence in patients with chronic kidney failure could be potentially rescued by the administration of melatonin, which grants this hormone a novel therapeutic role.

Keywords

References

  1. Abbas, M., Jesel, L., Auger, C., Amoura, L., Messas, N., Manin, G., Rumig, C., Leon-Gonzalez, A. J., Ribeiro, T. P., Silva, G. C., Abou-Merhi, R., Hamade, E., Hecker, M., Georg, Y., Chakfe, N., Ohlmann, P., Schini-Kerth, V. B., Toti, F. and Morel, O. (2017) Endothelial microparticles from acute coronary syndrome patients induce premature coronary artery endothelial cell aging and thrombogenicity: role of the Ang II/AT1 receptor/NADPH oxidase-mediated activation of MAPKs and PI3-kinase pathways. Circulation 135, 280-296. https://doi.org/10.1161/CIRCULATIONAHA.116.017513
  2. Acuna-Castroviejo, D., Escames, G., Venegas, C., Diaz-Casado, M. E., Lima-Cabello, E., Lopez, L. C., Rosales-Corral, S., Tan, D. X. and Reiter, R. J. (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell. Mol. Life Sci. 71, 2997-3025. https://doi.org/10.1007/s00018-014-1579-2
  3. Adams, W. C., Chen, Y. H., Kratchmarov, R., Yen, B., Nish, S. A., Lin, W. W., Rothman, N. J., Luchsinger, L. L., Klein, U., Busslinger, M., Rathmell, J. C., Snoeck, H. W. and Reiner, S. L. (2016) Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep. 17, 3142-3152. https://doi.org/10.1016/j.celrep.2016.11.065
  4. Altman, J. and Das, G. D. (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319-335. https://doi.org/10.1002/cne.901240303
  5. Azevedo, M. L., Bonan, N. B., Dias, G., Brehm, F., Steiner, T. M., Souza, W. M., Stinghen, A. E., Barreto, F. C., Elifio-Esposito, S., Pecoits-Filho, R. and Moreno-Amaral, A. N. (2016) p-Cresyl sulfate affects the oxidative burst, phagocytosis process, and antigen presentation of monocyte-derived macrophages. Toxicol. Lett. 263, 1-5. https://doi.org/10.1016/j.toxlet.2016.10.006
  6. Brocca, A., Virzi, G. M., de Cal, M., Cantaluppi, V. and Ronco, C. (2013) Cytotoxic effects of p-cresol in renal epithelial tubular cells. Blood Purif. 36, 219-225. https://doi.org/10.1159/000356370
  7. Cerini, C., Dou, L., Anfosso, F., Sabatier, F., Moal, V., Glorieux, G., De Smet, R., Vanholder, R., Dignat-George, F., Sampol, J., Berland, Y. and Brunet, P. (2004) P-cresol, a uremic retention solute, alters the endothelial barrier function in vitro. Thromb. Haemost. 92, 140-150.
  8. Chang, M. C., Chang, H. H., Chan, C. P., Yeung, S. Y., Hsien, H. C., Lin, B. R., Yeh, C. Y., Tseng, W. Y., Tseng, S. K. and Jeng, J. H. (2014) p-Cresol affects reactive oxygen species generation, cell cycle arrest, cytotoxicity and inflammation/atherosclerosis-related modulators production in endothelial cells and mononuclear cells. PLoS ONE 9, e114446. https://doi.org/10.1371/journal.pone.0114446
  9. Chua, S., Lee, F. Y., Chiang, H. J., Chen, K. H., Lu, H. I., Chen, Y. T., Yang, C. C., Lin, K. C., Chen, Y. L., Kao, G. S., Chen, C. H., Chang, H. W. and Yip, H. K. (2016) The cardioprotective effect of melatonin and exendin-4 treatment in a rat model of cardiorenal syndrome. J. Pineal Res. 61, 438-456. https://doi.org/10.1111/jpi.12357
  10. D'Hooge, R., Van de Vijver, G., Van Bogaert, P. P., Marescau, B., Vanholder, R. and De Deyn, P. P. (2003) Involvement of voltage- and ligand-gated $Ca^{2+}$ channels in the neuroexcitatory and synergistic effects of putative uremic neurotoxins. Kidney Int. 63, 1764-1775. https://doi.org/10.1046/j.1523-1755.2003.00912.x
  11. Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., Joshua, B., Kaplan, M. J., Wapnir, I., Dirbas, F. M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S. K., Quake, S. R., Brown, J. M., Weissman, I. L. and Clarke, M. F. (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780-783. https://doi.org/10.1038/nature07733
  12. Dou, L., Cerini, C., Brunet, P., Guilianelli, C., Moal, V., Grau, G., De Smet, R., Vanholder, R., Sampol, J. and Berland, Y. (2002) P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines. Kidney Int. 62, 1999-2009. https://doi.org/10.1046/j.1523-1755.2002.t01-1-00651.x
  13. Faure, V., Dou, L., Sabatier, F., Cerini, C., Sampol, J., Berland, Y., Brunet, P. and Dignat-George, F. (2006) Elevation of circulating endothelial microparticles in patients with chronic renal failure. J. Thromb. Haemost. 4, 566-573. https://doi.org/10.1111/j.1538-7836.2005.01780.x
  14. Fernandez, A., Ordonez, R., Reiter, R. J., Gonzalez-Gallego, J. and Mauriz, J. L. (2015) Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J. Pineal Res. 59, 292-307. https://doi.org/10.1111/jpi.12264
  15. Fu, J., Zhao, S. D., Liu, H. J., Yuan, Q. H., Liu, S. M., Zhang, Y. M., Ling, E. A. and Hao, A. J. (2011) Melatonin promotes proliferation and differentiation of neural stem cells subjected to hypoxia in vitro. J. Pineal Res. 51, 104-112. https://doi.org/10.1111/j.1600-079X.2011.00867.x
  16. Gabriele, S., Sacco, R., Altieri, L., Neri, C., Urbani, A., Bravaccio, C., Riccio, M. P., Iovene, M. R., Bombace, F., De Magistris, L. and Persico, A. M. (2016) Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children. Autism Res. 9, 752-759. https://doi.org/10.1002/aur.1571
  17. Ganesan, R., Hos, N. J., Gutierrez, S., Fischer, J., Stepek, J. M., Daglidu, E., Kronke, M. and Robinson, N. (2017) Salmonella Typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy. PLoS Pathog. 13, e1006227. https://doi.org/10.1371/journal.ppat.1006227
  18. Hardeland, R., Pandi-Perumal, S. R. and Cardinali, D. P. (2006) Melatonin. Int. J. Biochem. Cell Biol. 38, 313-316. https://doi.org/10.1016/j.biocel.2005.08.020
  19. Kang, J. W., Cho, H. I. and Lee, S. M. (2014) Melatonin inhibits mTOR-dependent autophagy during liver ischemia/reperfusion. Cell. Physiol. Biochem. 33, 23-36. https://doi.org/10.1159/000356647
  20. Kim, C. H., Kim, K. H. and Yoo, Y. M. (2011) Melatonin protects against apoptotic and autophagic cell death in C2C12 murine myoblast cells. J. Pineal Res. 50, 241-249. https://doi.org/10.1111/j.1600-079X.2010.00833.x
  21. Kim, C. H., Kim, K. H. and Yoo, Y. M. (2012) Melatonin-induced autophagy is associated with degradation of MyoD protein in C2C12 myoblast cells. J. Pineal Res. 53, 289-297. https://doi.org/10.1111/j.1600-079X.2012.00998.x
  22. Krause, D. S., Theise, N. D., Collector, M. I., Henegariu, O., Hwang, S., Gardner, R., Neutzel, S. and Sharkis, S. J. (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369-377. https://doi.org/10.1016/S0092-8674(01)00328-2
  23. Lee, S. J., Jung, Y. H., Oh, S. Y., Yun, S. P. and Han, H. J. (2014) Melatonin enhances the human mesenchymal stem cells motility via melatonin receptor 2 coupling with $G{\alpha}q$ in skin wound healing. J. Pineal Res. 57, 393-407. https://doi.org/10.1111/jpi.12179
  24. Lesniewski, L. A., Seals, D. R., Walker, A. E., Henson, G. D., Blimline, M. W., Trott, D. W., Bosshardt, G. C., LaRocca, T. J., Lawson, B. R., Zigler, M. C. and Donato, A. J. (2017) Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 16, 17-26. https://doi.org/10.1111/acel.12524
  25. Li, W., Saud, S. M., Young, M. R., Chen, G. and Hua, B. (2015) Targeting AMPK for cancer prevention and treatment. Oncotarget 6, 7365-7378.
  26. Liang, Q., Luo, Z., Zeng, J., Chen, W., Foo, S. S., Lee, S. A., Ge, J., Wang, S., Goldman, S. A., Zlokovic, B. V., Zhao, Z. and Jung, J. U. (2016) Zika virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy. Cell Stem Cell 19, 663-671. https://doi.org/10.1016/j.stem.2016.07.019
  27. Lin, H. H., Huang, C. C., Lin, T. Y. and Lin, C. Y. (2015) p-Cresol mediates autophagic cell death in renal proximal tubular cells. Toxicol. Lett. 234, 20-29. https://doi.org/10.1016/j.toxlet.2015.02.003
  28. Maiese, K. (2016) Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br. J. Clin. Pharmacol. 82, 1245-1266. https://doi.org/10.1111/bcp.12804
  29. Martin, V., Sanchez-Sanchez, A. M., Puente-Moncada, N., Gomez-Lobo, M., Alvarez-Vega, M. A., Antolin, I. and Rodriguez, C. (2014) Involvement of autophagy in melatonin-induced cytotoxicity in glioma-initiating cells. J. Pineal Res. 57, 308-316. https://doi.org/10.1111/jpi.12170
  30. Maruyama, N., Ishigami, A. and Kondo, Y. (2010) Pathophysiological significance of senescence marker protein-30. Geriatr. Gerontol. Int. 10 Suppl 1, S88-S98. https://doi.org/10.1111/j.1447-0594.2010.00586.x
  31. Maung, S. C., El Sara, A., Chapman, C., Cohen, D. and Cukor, D. (2016) Sleep disorders and chronic kidney disease. World J. Nephrol. 5, 224-232. https://doi.org/10.5527/wjn.v5.i3.224
  32. Mehrzadi, S., Safa, M., Kamrava, S. K., Darabi, R., Hayat, P. and Motevalian, M. (2016) Protective mechanisms of melatonin against hydrogen peroxide induced toxicity in human bone-marrow derived mesenchymal stem cells. Can. J. Physiol. Pharmacol. [Epub ahead of print].
  33. Meijers, B. K., Claes, K., Bammens, B., de Loor, H., Viaene, L., Verbeke, K., Kuypers, D., Vanrenterghem, Y. and Evenepoel, P. (2010) p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin. J. Am. Soc. Nephrol. 5, 1182-1189. https://doi.org/10.2215/CJN.07971109
  34. Menendez, J. A., Vellon, L., Oliveras-Ferraros, C., Cufi, S. and Vazquez-Martin, A. (2011) mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle 10, 3658-3677. https://doi.org/10.4161/cc.10.21.18128
  35. Michalik, A. and Jarzyna, R. (2016) The key role of AMP-activated protein kinase (AMPK) in aging process. Postepy Biochem. 62, 459-471.
  36. Neirynck, N., Vanholder, R., Schepers, E., Eloot, S., Pletinck, A. and Glorieux, G. (2013) An update on uremic toxins. Int. Urol. Nephrol. 45, 139-150. https://doi.org/10.1007/s11255-012-0258-1
  37. Noh, H., Yu, M. R., Kim, H. J., Jang, E. J., Hwang, E. S., Jeon, J. S., Kwon, S. H. and Han, D. C. (2014) Uremic toxin p-cresol induces Akt-pathway-selective insulin resistance in bone marrow-derived mesenchymal stem cells. Stem Cells 32, 2443-2453. https://doi.org/10.1002/stem.1738
  38. Park, J., Lee, H., Lee, H. J., Kim, G. C., Kim, D. Y., Han, S. and Song, K. (2016a) Non-thermal atmospheric pressure plasma efficiently promotes the proliferation of adipose tissue-derived stem cells by activating NO-response pathways. Sci. Rep. 6, 39298. https://doi.org/10.1038/srep39298
  39. Park, J. H., Choi, S. H., Kim, H., Ji, S. T., Jang, W. B., Kim, J. H., Baek, S. H. and Kwon, S. M. (2016b) Doxorubicin regulates autophagy signals via accumulation of cytosolic $Ca^{2+}$ in human cardiac progenitor cells. Int. J. Mol. Sci. 17, E1680. https://doi.org/10.3390/ijms17101680
  40. Phinney, D. G. and Prockop, D. J. (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells 25, 2896-2902. https://doi.org/10.1634/stemcells.2007-0637
  41. Qiao, C., Xu, W., Zhu, W., Hu, J., Qian, H., Yin, Q., Jiang, R., Yan, Y., Mao, F., Yang, H., Wang, X. and Chen, Y. (2008) Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol. Int. 32, 8-15. https://doi.org/10.1016/j.cellbi.2007.08.002
  42. Reiter, R. J. and Tan, D. X. (2003) What constitutes a physiological concentration of melatonin? J. Pineal Res. 34, 79-80. https://doi.org/10.1034/j.1600-079X.2003.2e114.x
  43. Riva, B., De Dominici, M., Gnemmi, I., Mariani, S. A., Minassi, A., Minieri, V., Salomoni, P., Canonico, P. L., Genazzani, A. A., Calabretta, B. and Condorelli, F. (2016) Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of ${\beta}$-catenin and mTORC1/2. Oncotarget 7, 81555-81570. https://doi.org/10.18632/oncotarget.13146
  44. Till, J. E. and Mc, C. E. (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213-222. https://doi.org/10.2307/3570892
  45. Watanabe, H., Miyamoto, Y., Honda, D., Tanaka, H., Wu, Q., Endo, M., Noguchi, T., Kadowaki, D., Ishima, Y., Kotani, S., Nakajima, M., Kataoka, K., Kim-Mitsuyama, S., Tanaka, M., Fukagawa, M., Otagiri, M. and Maruyama, T. (2013) p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int. 83, 582-592. https://doi.org/10.1038/ki.2012.448
  46. Yang, Z. J., Chee, C. E., Huang, S. and Sinicrope, F. A. (2011) The role of autophagy in cancer: therapeutic implications. Mol. Cancer Ther. 10, 1533-1541. https://doi.org/10.1158/1535-7163.MCT-11-0047
  47. Yu, L., Gong, B., Duan, W., Fan, C., Zhang, J., Li, Z., Xue, X., Xu, Y., Meng, D., Li, B., Zhang, M., Bin, Z., Jin, Z., Yu, S., Yang, Y. and Wang, H. (2017) Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-$1{\alpha}$-SIRT3 signaling. Sci. Rep. 7, 41337. https://doi.org/10.1038/srep41337
  48. Yun, S. P., Lee, M. Y., Ryu, J. M., Song, C. H. and Han, H. J. (2009) Role of HIF-1alpha and VEGF in human mesenchymal stem cell proliferation by 17beta-estradiol: involvement of PKC, PI3K/Akt, and MAPKs. Am. J. Physiol. Cell Physiol. 296, C317-C326. https://doi.org/10.1152/ajpcell.00415.2008
  49. Zhang, L., Su, P., Xu, C., Chen, C., Liang, A., Du, K., Peng, Y. and Huang, D. (2010) Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing $PPAR{\gamma}$ expression and enhancing Runx2 expression. J. Pineal Res. 49, 364-372. https://doi.org/10.1111/j.1600-079X.2010.00803.x
  50. Zhao, H., Kalivendi, S., Zhang, H., Joseph, J., Nithipatikom, K., Vasquez-Vivar, J. and Kalyanaraman, B. (2003) Superoxide reacts with hydroethidine but forms a fluorescent product that is distinctly different from ethidium: potential implications in intracellular fluorescence detection of superoxide. Free Radic. Biol. Med. 34, 1359-1368. https://doi.org/10.1016/S0891-5849(03)00142-4
  51. Zielonka, J., Srinivasan, S., Hardy, M., Ouari, O., Lopez, M., Vasquez-Vivar, J., Avadhani, N. G. and Kalyanaraman, B. (2008) Cytochrome c-mediated oxidation of hydroethidine and mito-hydroethidine in mitochondria: identification of homo- and heterodimers. Free Radic. Biol. Med. 44, 835-846. https://doi.org/10.1016/j.freeradbiomed.2007.11.013

Cited by

  1. -dependent enhancement of the mitochondrial function pp.07423098, 2019, https://doi.org/10.1111/jpi.12535
  2. Melatonin prevents chronic intermittent hypoxia-induced injury by inducing sirtuin 1-mediated autophagy in steatotic liver of mice pp.1522-1709, 2018, https://doi.org/10.1007/s11325-018-1741-4
  3. Melatonin protects vertebral endplate chondrocytes against apoptosis and calcification via the Sirt1-autophagy pathway pp.15821838, 2018, https://doi.org/10.1111/jcmm.13903
  4. Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3 vol.19, pp.8, 2018, https://doi.org/10.3390/ijms19082439
  5. Co-Administration of Melatonin Effectively Enhances the Therapeutic Effects of Pioglitazone on Mesenchymal Stem Cells Undergoing Indoxyl Sulfate-Induced Senescence through Modulation of Cellular Prion Protein Expression vol.19, pp.5, 2018, https://doi.org/10.3390/ijms19051367
  6. Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis vol.16, pp.4, 2018, https://doi.org/10.3390/md16040121
  7. Melatonin plays critical role in mesenchymal stem cell-based regenerative medicine in vitro and in vivo vol.10, pp.1, 2019, https://doi.org/10.1186/s13287-018-1114-8
  8. Insights on Melatonin as an Active Pharmacological Molecule in Cancer Prevention: What’s New? vol.26, pp.34, 2018, https://doi.org/10.2174/0929867325666180501094850
  9. Pioglitazone Improves the Function of Human Mesenchymal Stem Cells in Chronic Kidney Disease Patients vol.20, pp.9, 2019, https://doi.org/10.3390/ijms20092314
  10. Effect of aging on behaviour of mesenchymal stem cells vol.11, pp.6, 2018, https://doi.org/10.4252/wjsc.v11.i6.337
  11. Melatonin‐mediated regulation of autophagy: Making sense of double‐edged sword in cancer vol.234, pp.10, 2019, https://doi.org/10.1002/jcp.28435
  12. Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging vol.8, pp.None, 2020, https://doi.org/10.3389/fcell.2020.00107
  13. Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases vol.10, pp.8, 2018, https://doi.org/10.3390/biom10081158
  14. Melatonin Suppresses Renal Cortical Fibrosis by Inhibiting Cytoskeleton Reorganization and Mitochondrial Dysfunction through Regulation of miR-4516 vol.21, pp.15, 2018, https://doi.org/10.3390/ijms21155323
  15. Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites vol.22, pp.2, 2018, https://doi.org/10.3390/ijms22020697
  16. Autophagy: a promising therapeutic target for improving mesenchymal stem cell biological functions vol.476, pp.2, 2021, https://doi.org/10.1007/s11010-020-03978-2