Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker

Al‑Kafaji,Ghada; Al‑Mahroos,Ghazi; Al‑Muhtaresh,Haifa  Abdulla; Skrypnyk,Cristina; Sabry,Mohamed  Abdalla; Ramadan,Ahmad  R.

doi:10.3892/etm.2016.3395

Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker

Authors:
- Ghada Al‑Kafaji
- Ghazi Al‑Mahroos
- Haifa Abdulla Al‑Muhtaresh
- Cristina Skrypnyk
- Mohamed Abdalla Sabry
- Ahmad R. Ramadan
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Affiliations: Department of Molecular Medicine/Al‑Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain, Diabetes and Endocrinology Clinic, Salmaniya Medical Complex, Manama 12, Kingdom of Bahrain, Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain, Department of Life Sciences, Medical Biotechnology, College of Graduate Studies, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
Published online on: May 26, 2016 https://doi.org/10.3892/etm.2016.3395
Pages: 815-822

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Abstract

Circulating microRNAs (miRNAs) have been proposed as promising biomarkers for multiple diseases. miR-126 is reported to be associated with type 2 diabetes mellitus (T2D), diabetic nephropathy (DN) and end stage renal disease. The aim of this study was to investigate the expression of circulating miR‑126 and to assess its potential as a blood‑based biomarker for DN in T2D patients. In 52 patients with T2D without history of DN (with noromoalbuminuria), 50 patients with T2D and DN (29 with microalbuminuria and 21 with macroalbuminuria), and 50 non-diabetic healthy controls, the expression of circulating miR‑126 in peripheral whole blood was evaluated by quantitative polymerase chain reaction. The expression levels of circulating miR‑126 were significantly decreased in T2D patients and further decreased in DN patients compared with those in the controls. Multivariate logistic regression analysis confirmed the independent association of lower miR‑126 levels with T2D [adjusted odds ratio (OR), 0.797; 95% confidence interval (CI), 0.613‑0.960] and DN (adjusted OR, 0.513; 95% CI, 0.371‑0.708). miR‑126 levels were associated with the degree of albuminuria and showed significantly low expression in DN patients with microalbuminuria (adjusted OR, 0.781; 95% CI; 0.698‑0.952) and further lower expression in DN patients with macroalbuminuria (adjusted OR, 0.433; 95% CI, 0.299‑0.701), respectively compared with T2D patients with normoalbuminuria. miR‑126 levels negatively correlated with albuminuria positively with glomerular filtration rate (P<0.05), and in addition, negatively correlated with fasting glucose, glycated hemoglobin, triglyceride and LDL (P<0.05). Stepwise multiple regression analysis identified albuminuria as a significant predictor of miR‑126 (P<0.001). miR‑126 in peripheral blood yielded area under the receiver operating characteristic curves of 0.854 (95% CI, 0.779‑0.929) and 0.959 (95% CI, 0.916‑1.000) in the differentiation of DN patients from T2D patients and DN patients from non‑diabetic controls respectively. These data suggest that decreased expression of circulating miR‑126 is associated with the development of DN in T2D patients, and may be a promising blood‑based biomarker for DN risk estimation.

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1	Declèves AE and Sharma K: New pharmacological treatments for improving renal outcomes in diabetes. Nat Rev Nephrol. 6:371–380. 2010. View Article : Google Scholar : PubMed/NCBI
2	Ruggenenti P and Remuzzi G: Nephropathy of type 1 and type 2 diabetes: Diverse pathophysiology, same treatment? Nephrol Dial Transplant. 15:1900–1902. 2000. View Article : Google Scholar : PubMed/NCBI
3	Kanwar YS, Sun L, Xie P, Liu FY and Chen S: A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 6:395–423. 2011. View Article : Google Scholar : PubMed/NCBI
4	Cheng H and Harris RC: Renal endothelial dysfunction in diabetic nephropathy. Cardiovasc Hematol Disord Drug Targets. 14:22–33. 2014. View Article : Google Scholar : PubMed/NCBI
5	Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 310:356–360. 1984. View Article : Google Scholar : PubMed/NCBI
6	Rossing K, Christensen PK, Hovind P, Tarnowl L, Rossing P and Parving HH: Progression of nephropathy in type 2 diabetic patients. Kidney Int. 66:1596–1605. 2004. View Article : Google Scholar : PubMed/NCBI
7	Gonzalez Suarez ML, Thomas DB, Barisoni L and Fornoni A: Diabetic nephropathy: Is it time yet for routine kidney biopsy? World J Diabetes. 4:245–255. 2013.PubMed/NCBI
8	Hillege HL, Janseen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw D and De Jong PE: Prevend Study Group: Microalbuminuria is common, also in a nondiabetic, no hypertensive population and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 249:519–526. 2001. View Article : Google Scholar : PubMed/NCBI
9	Tabaei BP, Al-Kassab AS, Ilag LL, Zawacki CM and Herman WH: Does microalbuminuria predict diabetic nephropathy? Diabetes Care. 24:1560–1566. 2001. View Article : Google Scholar : PubMed/NCBI
10	Jeon YK, Kim MR, Huh JE, Mok JY, Song SH, Kim SS, Kim BH, Lee SH, Kim YK and Kim IJ: Cystatin C as an early biomarker of nephropathy in patients with type 2 diabetes. J Korean Med Sci. 26:258–263. 2011. View Article : Google Scholar : PubMed/NCBI
11	Oddoze C, Morange S, Portugal H, Berland Y and Dussol B: Cystatin C is not more sensitive than creatinine for detecting early renal impairment in patients with diabetes. Am J Kidney Dis. 38:310–316. 2001. View Article : Google Scholar : PubMed/NCBI
12	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
13	Pillai RS, Bhattacharyya SN and Filipowicz W: Repression of protein synthesis by miRNAs: How many mechanisms? Trends Cell Biol. 17:118–126. 2007. View Article : Google Scholar : PubMed/NCBI
14	Ardekani AM and Naeini M: The role of microRNAs in human diseases. Avicenna J Med Biotechnol. 2:161–179. 2010.PubMed/NCBI
15	Pandey AK, Agarwal P, Kaur K and Datta M: MicroRNAs in diabetes: Tiny players in big disease. Cell Physiol Biochem. 23:221–232. 2009. View Article : Google Scholar : PubMed/NCBI
16	Bhatt K, Mi QS and Dong Z: MicroRNAs in kidneys: Biogenesis, regulation, and pathophysiological roles. Am J Physiol Renal Physiol. 300:F602–F610. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kato M, Arce L and Natarajan R: MicroRNAs and their role in progressive kidney diseases. Clin J Am Soc Nephrol. 4:1255–1266. 2009. View Article : Google Scholar : PubMed/NCBI
18	Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ and Wang K: The microRNA spectrum in 12 body fluids. Clin Chem. 56:1733–1741. 2010. View Article : Google Scholar : PubMed/NCBI
19	Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, et al: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 105:10513–10518. 2008. View Article : Google Scholar : PubMed/NCBI
20	Etheridge A, Lee I, Hood L, Galas D and Wang K: Extracellular microRNA: A new source of biomarkers. Mutat Res. 717:85–90. 2011. View Article : Google Scholar : PubMed/NCBI
21	Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo L, Zhang Y, Chen J, Guo X, et al: Characterization of microRNAs in serum: A novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18:997–1006. 2008. View Article : Google Scholar : PubMed/NCBI
22	Al-Kafaji G, Al-Mahroos G, Alsayed NA, Hasan ZA, Nawaz S and Bakhiet M: Peripheral blood microRNA-15a is a potential biomarker for type 2 diabetes mellitus and pre-diabetes. Mol Med Rep. 12:7485–7490. 2015.PubMed/NCBI
23	Meder B, Keller A, Vogel B, Haas J, Sedaghat-Hameddani F, Kayvanpour E, Just S, Borries A, Rudloff J, Leidinger P, et al: MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction. Basic Res Cardiol. 106:13–23. 2011. View Article : Google Scholar : PubMed/NCBI
24	Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R and Olson EN: The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 15:261–271. 2008. View Article : Google Scholar : PubMed/NCBI
25	Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, et al: Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 107:810–817. 2010. View Article : Google Scholar : PubMed/NCBI
26	Ortega FJ, Mercader JM, Moreno-Navarrete JM, Rovira O, Guerra E, Esteve E, Xifra G, Martínez C, Ricart W, Rieusset J, et al: Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care. 37:1375–1383. 2014. View Article : Google Scholar : PubMed/NCBI
27	Liu Y, Gao G, Yang C, Zhou K, Shen B, Liang H and Jiang X: The role of circulating microRNA-126 (miR-126): A novel biomarker for screening prediabetes and newly diagnosed type 2 diabetes mellitus. Int J Mol Sci. 15:10567–10577. 2014. View Article : Google Scholar : PubMed/NCBI
28	Bijkerk R, Duijs JM, Khairoun M, Ter Horst CJ, van der Pol P, Mallat MJ, Rotmans JI, de Vries AP, de Koning EJ, de Fijter JW, et al: Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas-kidney transplantation. Am J Transplant. 15:1081–1090. 2015. View Article : Google Scholar : PubMed/NCBI
29	Wang H, Peng W, Shen X, Huang Y, Ouyang X and Dai Y: Circulating levels of inflammation-associated miR-155 and endothelial-enriched miR-126 in patients with end-stage renal disease. Braz J Med Biol Res. 45:1308–1314. 2012. View Article : Google Scholar : PubMed/NCBI
30	Alberti KG and Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 15:539–553. 1998. View Article : Google Scholar : PubMed/NCBI
31	Stoves J, Lindley EJ, Barnfield MC, Burniston MT and Newstead CG: MDRD equation estimates of glomerular filtration rate in potential living kidney donors and renal transplant recipients with impaired graft function. Nephrol Dial Transplant. 17:2036–2037. 2002. View Article : Google Scholar : PubMed/NCBI
32	Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ and Lötvall JO: Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 9:654–659. 2007. View Article : Google Scholar : PubMed/NCBI
33	Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y and Ochiya T: Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 285:17442–17452. 2010. View Article : Google Scholar : PubMed/NCBI
34	Chen X, Liang H, Zhang J, Zen K and Zhang CY: Secreted microRNAs: A new form of intercellular communication. Trends Cell Biol. 22:125–132. 2012. View Article : Google Scholar : PubMed/NCBI
35	Liu Y, Gao G, Yang C, Zhou K, Shen B, Liang H and Jiang X: Stability of miR-126 in urine and its potential as a biomarker for renal endothelial injury with diabetic nephropathy. Int J Endocrinol. 2014:3931092014. View Article : Google Scholar : PubMed/NCBI
36	Osipova J, Fischer DC, Dangwal S, Volkmann I, Widera C, Schwarz K, Lorenzen JM, Schreiver C, Jacoby U, Heimhalt M, et al: Diabetes-associated microRNAs in pediatric patients with type 1 diabetes mellitus: A cross-sectional cohort study. J Clin Endocrinol Metab. 99:E1661–E1665. 2014. View Article : Google Scholar : PubMed/NCBI
37	Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY and Srivastava D: MiR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 15:272–284. 2008. View Article : Google Scholar : PubMed/NCBI
38	Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Köppel T, Jahantigh MN, Lutgens E, et al: Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2:ra812009. View Article : Google Scholar : PubMed/NCBI
39	Harvey SJ, Jarad G, Cunningham J, Goldberg S, Schermer B, Harfer BD, McManus MT, Benzing T and Miner JH: Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease. J Am Soc Nephrol. 19:2150–2158. 2008. View Article : Google Scholar : PubMed/NCBI
40	Meng S, Cao JT, Zhang B, Zhou Q, Shen CX and Wang CQ: Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. J Mol Cell Cardiol. 53:64–72. 2012. View Article : Google Scholar : PubMed/NCBI
41	Harris TA, Yamakuchi M, Ferlito M, Mendell JT and Lowenstein CJ: MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA. 105:1516–1521. 2008. View Article : Google Scholar : PubMed/NCBI
42	Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W and Tuschl T: Identification of tissue-specific microRNAs from mouse. Curr Biol. 12:735–739. 2002. View Article : Google Scholar : PubMed/NCBI
43	Jiang Y, Wang HY, Li Y, Guo SH, Zhang L and Cai JH: Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases. Sci Rep. 4:50262014.PubMed/NCBI
44	Asgeirsdóttir SA, van Solingen C, Kurniati NF, Zwiers PJ, Heeringa P, van Meurs M, Satchell SC, Saleem MA, Mathieson PW, Banas B, et al: MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation. Am J Physiol Renal Physiol. 302:F1630–F1639. 2012. View Article : Google Scholar : PubMed/NCBI
45	Hostetter TH: Prevention of the development and progression of renal disease. J Am Soc Nephrol. 14(7 Suppl 2): S144–S147. 2003. View Article : Google Scholar : PubMed/NCBI