A Cross-Sectional Study of p66Shc Gene Expression in Liquid Biopsy of Diabetic Patients. Is it Possible to Predict the Onset of Renal Disease?
DOI:
https://doi.org/10.5195/ijms.2022.1306Keywords:
Diabetes Mellitus, P66Shc, Biomarker, Liquid Biopsy.Abstract
Background: Diabetic nephropathy (DN) is a disorder affecting glomerular function that, histologically, is due to the presence of glomerulosclerosis accompanied with endothelial dysfunction of the afferent and efferent renal arterioles. Insulin resistance in diabetic patients is known to be one of the causes of endothelial dysfunction because it increases oxidative stress, and one of the main genes regulating the production pathways of reactive oxygen species is p66Shc. The aim of this study was to evaluate the p66Shc gene expression as a precocious biomarker of renal dysfunction in diabetic patients, using liquids samples of urine sediment and peripheral blood.
Methods: 29 diabetic patients and 37 healthy donors were recruited from the Centro Universitário FMABC outpatient clinic. The RT-gPCR technique was applied to evaluate p66Shc gene expression in urine and peripheral blood samples from diabetic patients, which were compared with healthy donors.
Results: There was no significant expression of p66Shc gene in samples from diabetic patients compared with healthy donors. However, p66Shc expression in the blood samples of diabetics (0.02417±0.078652-ΔCT, n=29) was 3.6 times higher than in healthy participants (0.00689±0.01758, n=37) while in the urine samples, it was 1.48 times higher in diabetics group (0.02761±0.05412-ΔCT) than in CTL group (0.0186±0.02199).
Conclusion: There was no significant p66Shc gene expression in peripheral blood and urine samples of diabetic patients without kidney injury compared with healthy donors, although there is a tendency for this gene to participate in the oxidative imbalance present in diabetes.
Metrics
References
de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2014;37(10):2843-63. DOI: https://doi.org/10.2337/dc14-1720
Maraschin JeF. Classification of diabetes. Adv Exp Med Biol. 2012;771:12-9. DOI: https://doi.org/10.1007/978-1-4614-5441-0_2
Li YR, Tsai SS, Lin YS, Chung CM, Chen ST, Sun JH, et al. Moderate- to high-intensity statins for secondary prevention in patients with type 2 diabetes mellitus on dialysis after acute myocardial infarction. Diabetol Metab Syndr. 2017;9:71. DOI: https://doi.org/10.1186/s13098-017-0272-7
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44 Suppl 2:S14-21. DOI: https://doi.org/10.1007/PL00002934
Selby JV, FitzSimmons SC, Newman JM, Katz PP, Sepe S, Showstack J. The natural history and epidemiology of diabetic nephropathy. Implications for prevention and control. JAMA. 1990;263(14):1954-60. DOI: https://doi.org/10.1001/jama.263.14.1954
Ma J, Wu H, Zhao CY, Panchapakesan U, Pollock C, Chadban SJ. Requirement for TLR2 in the development of albuminuria, inflammation and fibrosis in experimental diabetic nephropathy. Int J Clin Exp Pathol. 2014;7(2):481-95.
Romero-Aroca P. Targeting the pathophysiology of diabetic macular edema. Diabetes Care. 2010;33(11):2484-5. DOI: https://doi.org/10.2337/dc10-1580
Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80(1):17-28. DOI: https://doi.org/10.1038/ki.2010.483
Nacci C, Tarquinio M, Montagnani M. Molecular and clinical aspects of endothelial dysfunction in diabetes. Intern Emerg Med. 2009;4(2):107-16. DOI: https://doi.org/10.1007/s11739-009-0234-7
Murkamilov IT, Sabirov IS, Fomin VV, Yusupov FA. [Endothelial dysfunction and arterial wall stiffness: New targets in diabetic nephropathy]. Ter Arkh. 2017;89(10):87-94. DOI: https://doi.org/10.17116/terarkh2017891087-94
Fadini GP, Albiero M, Menegazzo L, Boscaro E, Pagnin E, Iori E, et al. The redox enzyme p66Shc contributes to diabetes and ischemia-induced delay in cutaneous wound healing. Diabetes. 2010;59(9):2306-14. DOI: https://doi.org/10.2337/db09-1727
Magenta A, Greco S, Capogrossi MC, Gaetano C, Martelli F. Nitric oxide, oxidative stress, and p66Shc interplay in diabetic endothelial dysfunction. Biomed Res Int. 2014;2014:193095. DOI: https://doi.org/10.1155/2014/193095
Poulet G, Massias J, Taly V. Liquid Biopsy: General Concepts. Acta Cytol. 2019;63(6):449-55. DOI: https://doi.org/10.1159/000499337
Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016;6(5):479-91. DOI: https://doi.org/10.1158/2159-8290.CD-15-1483
Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol. 2019;16(7):409-24. DOI: https://doi.org/10.1038/s41571-019-0187-3
Pan HZ, Zhang L, Guo MY, Sui H, Li H, Wu WH, et al. The oxidative stress status in diabetes mellitus and diabetic nephropathy. Acta Diabetol. 2010;47 Suppl 1:71-6. DOI: https://doi.org/10.1007/s00592-009-0128-1
Palmirotta R, Lovero D, Cafforio P, Felici C, Mannavola F, Pellè E, et al. Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology. Ther Adv Med Oncol. 2018;10:1758835918794630. DOI: https://doi.org/10.1177/1758835918794630
Kim SS, Song SH, Kim IJ, Jeon YK, Kim BH, Kwak IS, et al. Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy. Diabetes Care. 2013;36(3):656-61. DOI: https://doi.org/10.2337/dc12-0849
Grimaldi V, Vietri MT, Schiano C, Picascia A, De Pascale MR, Fiorito C, et al. Epigenetic reprogramming in atherosclerosis. Curr Atheroscler Rep. 2015;17(2):476. DOI: https://doi.org/10.1007/s11883-014-0476-3
Kim CS, Kim YR, Naqvi A, Kumar S, Hoffman TA, Jung SB, et al. Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc. Cardiovasc Res. 2011;92(3):466-75. DOI: https://doi.org/10.1093/cvr/cvr250
Xiao Y, Xia J, Cheng J, Huang H, Zhou Y, Yang X, et al. Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway. Circulation. 2019;139(19):2260-77. DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.036336
Camici GG, Schiavoni M, Francia P, Bachschmid M, Martin-Padura I, Hersberger M, et al. Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc Natl Acad Sci U S A. 2007;104(12):5217-22. DOI: https://doi.org/10.1073/pnas.0609656104
Menini S, Iacobini C, Ricci C, Oddi G, Pesce C, Pugliese F, et al. Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation. Diabetologia. 2007;50(9):1997-2007. DOI: https://doi.org/10.1007/s00125-007-0728-7
Menini S, Amadio L, Oddi G, Ricci C, Pesce C, Pugliese F, et al. Erratum. Deletion of p66. Diabetes. 2018;67(1):165. DOI: https://doi.org/10.2337/db18-er01a
Zaccagnini G, Martelli F, Fasanaro P, Magenta A, Gaetano C, Di Carlo A, et al. p66ShcA modulates tissue response to hindlimb ischemia. Circulation. 2004;109(23):2917-23. DOI: https://doi.org/10.1161/01.CIR.0000129309.58874.0F
Naldini A, Morena E, Pucci A, Pellegrini M, Baldari CT, Pelicci PG, et al. The adaptor protein p66Shc is a positive regulator in the angiogenic response induced by hypoxic T cells. J Leukoc Biol. 2010;87(3):365-9. DOI: https://doi.org/10.1189/jlb.0709460
Xu X, Zhu X, Ma M, Han Y, Hu C, Yuan S, et al. p66Shc: A novel biomarker of tubular oxidative injury in patients with diabetic nephropathy. Sci Rep. 2016;6:29302. DOI: https://doi.org/10.1038/srep29302
Veiga G, Alves B, Perez M, et al. NGAL and SMAD1 gene expression in the early detection of diabetic nephropathy by liquid biopsy. J Clin Pathol. 2020;73(11):713-721. DOI: https://doi.org/10.1136/jclinpath-2020-206494
Matsubara T, Araki M, Abe H, Ueda O, Jishage K, Mima A, et al. Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy. Diabetes. 2015;64(8):2978-90. DOI: https://doi.org/10.2337/db14-0893
Published
How to Cite
License
Copyright (c) 2022 Diogo Pimenta Simões, Matheus Moreira Perez, Beatriz da Costa Aguiar Alves, Jéssica Freitas Araújo Encinas, Joyce Regina Santos Raimundo, Catherine Giovanna Costas Arcia, Vanessa Lopes Mathia, Maria Isabel Sacchi Mendonça, Laura Beatriz Mesiano Maifrino, Neif Murad, Fernando Luiz Affonso Fonseca, Glaucia Luciano da Veiga
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- The Author retains copyright in the Work, where the term “Work” shall include all digital objects that may result in subsequent electronic publication or distribution.
- Upon acceptance of the Work, the author shall grant to the Publisher the right of first publication of the Work.
- The Author shall grant to the Publisher and its agents the nonexclusive perpetual right and license to publish, archive, and make accessible the Work in whole or in part in all forms of media now or hereafter known under a Creative Commons Attribution 4.0 International License or its equivalent, which, for the avoidance of doubt, allows others to copy, distribute, and transmit the Work under the following conditions:
- Attribution—other users must attribute the Work in the manner specified by the author as indicated on the journal Web site; with the understanding that the above condition can be waived with permission from the Author and that where the Work or any of its elements is in the public domain under applicable law, that status is in no way affected by the license.
- The Author is able to enter into separate, additional contractual arrangements for the nonexclusive distribution of the journal's published version of the Work (e.g., post it to an institutional repository or publish it in a book), as long as there is provided in the document an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post online a prepublication manuscript (but not the Publisher’s final formatted PDF version of the Work) in institutional repositories or on their Websites prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work. Any such posting made before acceptance and publication of the Work shall be updated upon publication to include a reference to the Publisher-assigned DOI (Digital Object Identifier) and a link to the online abstract for the final published Work in the Journal.
- Upon Publisher’s request, the Author agrees to furnish promptly to Publisher, at the Author’s own expense, written evidence of the permissions, licenses, and consents for use of third-party material included within the Work, except as determined by Publisher to be covered by the principles of Fair Use.
- The Author represents and warrants that:
- the Work is the Author’s original work;
- the Author has not transferred, and will not transfer, exclusive rights in the Work to any third party;
- the Work is not pending review or under consideration by another publisher;
- the Work has not previously been published;
- the Work contains no misrepresentation or infringement of the Work or property of other authors or third parties; and
- the Work contains no libel, invasion of privacy, or other unlawful matter.
- The Author agrees to indemnify and hold Publisher harmless from the Author’s breach of the representations and warranties contained in Paragraph 6 above, as well as any claim or proceeding relating to Publisher’s use and publication of any content contained in the Work, including third-party content.
Enforcement of copyright
The IJMS takes the protection of copyright very seriously.
If the IJMS discovers that you have used its copyright materials in contravention of the license above, the IJMS may bring legal proceedings against you seeking reparation and an injunction to stop you using those materials. You could also be ordered to pay legal costs.
If you become aware of any use of the IJMS' copyright materials that contravenes or may contravene the license above, please report this by email to contact@ijms.org
Infringing material
If you become aware of any material on the website that you believe infringes your or any other person's copyright, please report this by email to contact@ijms.org