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Methylglyoxal-derived advanced glycation end products induce matrix metalloproteinases through activation of ERK/JNK/NF-κB pathway in kidney proximal epithelial cells

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Abstract

The accumulation of reactive α-dicarbonyl leading to advanced glycation end products (AGEs) have been linked to pathophysiological diseases in many studies, such as atherosclerosis, cataract, cancer, and diabetic nephropathy. Glycation-generated AGEs increase the expression of inflammatory cytokines by transferring signals to the cell by binding them to the receptor for AGEs (RAGE) on their cell surface. The effect of methylglyoxal-derived AGEs (AGE-4) on the induction of matrix metalloproteinases (MMPs) in rat ordinary kidney cells (NRK-52E) was explored in this research, among other AGEs. The cell treated with 100 μg/mL AGE-4 for 24 h showed a substantial rise in MMP-2 and MMP-9 expression relative to BSA control only and other AGEs through ERK, JNK, and NF-B pathways. Our findings therefore suggest that AGE-4 expresses MMPs through the AGE-4-RAGE axis, activating MAPK signals that may contribute to dysfunction of the kidney cell.

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References

  • Ahmed N. Advanced glycation end products-role in pathology of diabetic complications. Diabetes Res. Clin. Pract. 67: 3-21 (2005)

    Article  CAS  Google Scholar 

  • Bhat S, Mary S, Giri AP, Kulkarni MJ. Advanced glycation end products (AGEs) in diabetic complications. In: Mechanisms of Vascular Defects in Diabetes Mellitus, vol 17, pp 423–449. Springer, Charm (2017)

  • Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP. Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. 83: 876-886 (2005)

    Article  CAS  Google Scholar 

  • Bourajjaj M, Stehouwer CDA, van Hinsbergh VWM, Schalkwijk CG. Role of methylglyoxal adducts in the development of vascular complications in diabetes mellitus. Biochem. Soc. Trans. 31: 1400-1402 (2003)

    Article  CAS  Google Scholar 

  • Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820 (2001)

    Article  CAS  Google Scholar 

  • Del Pozo CH, Shekhtman A, Ramasamy R, Schmidt AM. The receptor for advanced glycation final product: mechanism and treatment opportunity for obesity and diabetes. Enzym. Metab. J. 2: 1-10 (2017)

    Google Scholar 

  • Deng R, Mo F, Chang B, Zhang Q, Ran H, Yang S, Zhu Z, Hu L, Su Q. Glucose-derived AGEs enhance human gastric cancer metastasis through RAGE/ERK/Sp1/MMP2 cascade. Oncotarget 8: 104216-104226 (2017)

    Article  Google Scholar 

  • Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY. Transforming growth factor-beta regulates tubular epithelial-myofibroblast trans differentiation in vitro. Kidney Int. 56: 1455-1467 (1999)

    Article  CAS  Google Scholar 

  • Goh SY, Cooper ME. The role of advanced glycation end products in progression and complications of diabetes. J. Clin. Endocrinol. Metab. 93: 1143-1152 (2008)

    Article  CAS  Google Scholar 

  • Groener JB, Oikonomou D, Cheko R, Kender Z, Zemva J, Kihm L, Muckenthaler M, Peters V, Fleming T, Kopf S, Nawroth PP. Methylglyoxal and advanced glycation end products in patients with diabetes—what we know so far and the missing links. Exp. Clin. Endocrinol. Diabetes 1: 5-67 (2017)

    Google Scholar 

  • Ha YM, Chun SH, Hong ST, Koo YC, Choi HD, Lee KW. Immune enhancing effect of a Maillard-type lysozyme-galactomannan conjugate via signaling pathways. Int. J. Biol. Macromol. 60: 399-404 (2013)

    Article  CAS  Google Scholar 

  • Kanwar YS, Sun L, Xie P, Liu FY, Chen S. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu. Rev. Pathol. Mech. 6: 395-423 (2011)

    Article  CAS  Google Scholar 

  • Klein G, Vellenga E, Fraaije MW, Kampsa WA, de Bont ESJM. The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. Crit. Rev. Oncol. Hematol. 50: 87-100 (2004)

    Article  CAS  Google Scholar 

  • Linden E, Cai W, He JC, Xue C, Li Z, Winston J, Vlassara H, Uribarri J. Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation. Clin. J. Am. Soc. Nephrol. 3: 691-698 (2008)

    Article  CAS  Google Scholar 

  • Luo Y, Hara T, Ishido Y, Yoshihara A, Oda K, Makino M, Ishii N, Hiroi N, Suzuki K. Rapid preparation of high-purity nuclear proteins from a small number of cultured cells for use in electrophoretic mobility shift assays. BMC Immunol. 15: 586 (2014)

    Article  Google Scholar 

  • Makita Z, Vlassara H, Ceramai A, Bucala R. Immunochemical detection of advanced glycosylation end products in vivo. J. Biol Chem. 267: 5133-5138 (1992)

    CAS  PubMed  Google Scholar 

  • Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J. Am. Soc. Nephrol. 14: 1358-1373 (2003)

    Article  CAS  Google Scholar 

  • Pyo MC, Yang SY, Chun SH, Oh NS, Lee KW. Protective effects of Maillard reaction products of whey protein concentrate against oxidative stress through an Nrf2-dependent pathway in HepG2 cells. Biol. Pharm. Bull. 39: 1437-1447 (2016)

    Article  CAS  Google Scholar 

  • Rodrigues L, Matafome P, Crisóstomo J, Silva DS, Sena C, Pereira P, Seiça R. Advanced glycation end products and diabetic nephropathy:a comparative study using diabetic and normal rats with methylglyoxal-induced glycation. J. Physiol. Biochem. 70: 173-184 (2014)

    Article  CAS  Google Scholar 

  • Rojas A, Anazco C, Gonzalez I, Araya P. Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer. Carcinogenesis 39: 515-521 (2018)

    Article  CAS  Google Scholar 

  • Shi L, Yu X, Yang H, Wu X. Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways. Plos One 8: e66781 (2013)

    Article  CAS  Google Scholar 

  • Singh J, Chaudhari BP, Kakkar P. Baicalin and chrysin mixture imparts cyto-protection against methylglyoxal induced cytotoxicity and diabetic tubular injury by modulating RAGE, oxidative stress and inflammation. Environ. Toxicol. Pharmacol. 50: 67-75 (2017)

    Article  CAS  Google Scholar 

  • Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia 44: 129-146 (2001)

    Article  CAS  Google Scholar 

  • Stitt AW. Advanced glycation: an important pathological event in diabetic and age related ocular disease. Br. J. Ophthalmol. 85: 746-753 (2001)

    Article  CAS  Google Scholar 

  • Sun C, Liang C, Ren Y, Zhen Y, He Z, Wang H, Tan H, Pan X, Wu Z. Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic. Res. Cardiol. 104: 42-49 (2009)

    Article  CAS  Google Scholar 

  • Takeuchi M, Makita Z, Bucala R, Suzuki T, Koike T, Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo. Mol. Med. 6: 114-125 (2000)

    Article  CAS  Google Scholar 

  • Takeuchi M, Kikuchi S, Sasaki N, Suzuki T, Watai T, Iwaki M, Bucala R, Yamagishi SI. Involvement of advanced glycation end-products (AGEs) in Alzheimer’s disease. Curr. Alzheimer. Res. 1: 39-46 (2004)

    Article  CAS  Google Scholar 

  • Tan ALY, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin. Nephrol. 27: 130-143 (2007)

    Article  CAS  Google Scholar 

  • Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both?. Curr. Diab. Rep. 14: 453 (2014)

    Article  Google Scholar 

  • Xu X., Xiao L; Xiao P, Yang S, Chen G, Liu F, Kanwar YS, Sun L. A glimpse of matrix metalloproteinases in diabetic nephropathy. Curr. Med.Chem. 21: 3244-3260 (2014)

    Article  CAS  Google Scholar 

  • Xue J, Ray R, Singer D, Böhme D, Burz DS, Rai V, Hoffmann R, Shekhtman A. The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs. Biochemistry 53: 3327-3335 (2014)

    Article  CAS  Google Scholar 

  • Yu L, Zhang Y, Zhang H, Li Y. SOCS3 overexpression inhibits advanced glycation end product-induced EMT in proximal tubule epithelial cells. Exp.Ther. Med. 13: 3109-3115 (2007)

    Article  Google Scholar 

  • Zhang Q, Ames JM, Smith RD, Baynes JW, Metz TO. A perspective on the Maillard reaction and the analysis of protein glycation by mass spectrometry: probing the pathogenesis of chronic disease. J. Proteome. Res. 8: 754-769 (2009)

    Article  CAS  Google Scholar 

  • Zhu P, Ren M, Yang C, Hu YX, Ran JM, Yan L. Involvement of RAGE, MAPK and NF‐κB pathways in AGEs‐induced MMP‐9 activation in HaCaT keratinocytes. Exp. Dermatol. 21: 123-129 (2012)

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by Main Research Program (E0164400-04) of the Korea Food Research Institute (KFRI) funded by the Ministry of Science, ICT and Future Planning, the National Research Foundation of Korea grant funded by the Korea government (MEST) (No. 2017R1A2B4012182), Korea University Research Grant No. K1516071, and School of Life Sciences and Biotechnology of Korea University for BK21 PLUS. The authors are grateful to the Korea University-CJ Food Safety Center (Seoul, Republic of Korea) for allowing access to their equipment and facilities.

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Correspondence to Kwang-Won Lee.

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Jeong, SR., Park, HY., Kim, Y. et al. Methylglyoxal-derived advanced glycation end products induce matrix metalloproteinases through activation of ERK/JNK/NF-κB pathway in kidney proximal epithelial cells. Food Sci Biotechnol 29, 675–682 (2020). https://doi.org/10.1007/s10068-019-00704-7

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