Expression of microRNA‑377 and microRNA‑192 and their potential as blood‑based biomarkers for early detection of type 2 diabetic nephropathy

Al‑Kafaji,Ghada; Al‑Muhtaresh,Haifa   Abdulla

doi:10.3892/mmr.2018.9040

Expression of microRNA‑377 and microRNA‑192 and their potential as blood‑based biomarkers for early detection of type 2 diabetic nephropathy

Authors:
- Ghada Al‑Kafaji
- Haifa Abdulla Al‑Muhtaresh
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Affiliations: Department of Molecular Medicine and Al‑Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
Published online on: May 21, 2018 https://doi.org/10.3892/mmr.2018.9040
Pages: 1171-1180

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Abstract

The increased incidence of diabetic nephropathy (DN) in type 2 diabetes (T2D) requires novel markers for the early detection of DN. Previously, microRNAs (miRs) have been demonstrated to be promising disease biomarkers. The present study evaluated the biomarker potential of DN‑associated miR‑377 and miR‑192 in the early stages of DN. The study included 85 participants: 55 patients with T2D (30 without DN and 25 with DN) and 30 healthy controls. The patients with T2D were classified according to albumin‑to‑creatinine ratio and were split into three groups: Normoalbuminuric group (n=30), microalbuminuric group (n=15) and macroalbuminuric group (n=10). Reverse transcription‑quantitative polymerase chain reaction analysis was used to evaluate blood miR expression. It was observed that there was higher miR‑377 expression and lower miR‑192 expression in T2D patients with and without DN compared with healthy controls (P<0.05). miR‑377 was higher in the normoalbuminuric group and gradually increased in the microalbuminuric and macroalbuminuric groups (P<0.05), whereas miR‑192 was lower in the macroalbuminuric group compared with the normoalbuminuric group (P<0.05). Regression analysis revealed direct associations between the two miRs and albuminuria (P<0.05). miR‑377 was independently associated with DN risk, even following multivariable adjustment, and albuminuria was the only predictor of miR‑377 (P<0.001). In discriminating overall patients from healthy subjects, ROC analysis revealed areas under the curve (AUCs) of 0.851 for miR377 and 0.774 for miR‑192 (P<0.001). In discriminating the normoalbuminuric group from the microalbuminuric/macroalbuminuric groups, the AUCs were 0.711 (P=0.008) and 0.70 (P=0.049) for miR‑377 and miR‑192, respectively. In patients with microalbuminuria and macroalbuminuria, miR‑377 correlated positively with albuminuria and negatively with renal function, whereas miR‑192 correlated negatively with albuminuria and positively with renal function (P=0.001), and the two miRs were correlated with known risk factors of DN (P<0.05). The results suggested that blood‑based miR‑377 and miR‑192 may serve as potential biomarkers for early detection of DN. Further validation studies are required with larger sample sizes.

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1	Esteller M: Non-coding RNAs in human disease. Nat Rev Genet. 12:861–874. 2011. View Article : Google Scholar : PubMed/NCBI
2	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
3	Friedman RC, Farh KK, Burge CB and Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19:92–105. 2009. View Article : Google Scholar : PubMed/NCBI
4	Kloosterman WP and Plasterk RH: The diverse functions of microRNAs in animal development and disease. Dev Cell. 11:441–450. 2006. View Article : Google Scholar : PubMed/NCBI
5	Ha TY: MicroRNAs in human diseases: From cancer to cardiovascular disease. Immune Netw. 11:135–154. 2011. View Article : Google Scholar : PubMed/NCBI
6	Lorenzen J, Kumarswamy R, Dangwal S and Thum T: MicroRNAs in diabetes and diabetes-associated complications. RNA Biol. 9:820–827. 2012. View Article : Google Scholar : PubMed/NCBI
7	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
8	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
9	Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, Weller M and Keller A: A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem. 118:449–457. 2011. View Article : Google Scholar : PubMed/NCBI
10	Al-Kafaji G, Al Naieb ZT and Bakhiet M: Increased oncogenic microRNA-18a expression in peripheral blood of patients with prostate cancer: A potential role as new non-invasive biomarker. Oncol Lett. 11:1201–1206. 2016. View Article : Google Scholar : PubMed/NCBI
11	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. View Article : Google Scholar : PubMed/NCBI
12	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
13	Meder B, Keller A, Vogel B, Haas J, Sedaghat-Hamedani F, Kayyanpour 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
14	Al-Kafaji G, Al-Mahroos G, Al-Muhtaresh HA, Sabry MA, Razzak Abdul R and Salem AH: Circulating endothelium-enriched microRNA-126 as a potential biomarker for coronary artery disease in type 2 diabetes mellitus patients. Biomarkers. 22:268–278. 2017. View Article : Google Scholar : PubMed/NCBI
15	Shahbazian H and Rezaii I: Diabetic kidney disease; review of the current knowledge. J Renal Inj Prev. 2:73–80. 2013.PubMed/NCBI
16	Dronavalli S, Duka I and Bakris GL: The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab. 4:444–452. 2008. View Article : Google Scholar : PubMed/NCBI
17	Hu C, Sun L, Xiao L, Han Y, Fu X, Xiong X, Xu X, Liu Y, Yang S, Liu F and Kanwar YS: Insight into the mechanisms involved in the expression and regulation of extracellular matrix proteins in diabetic nephropathy. Curr Med Chem. 22:2858–2870. 2015. View Article : Google Scholar : PubMed/NCBI
18	Arora MK and Singh UK: Molecular mechanisms in the pathogenesis of diabetic nephropathy: An update. Vascul Pharmacol. 58:259–271. 2013. View Article : Google Scholar : PubMed/NCBI
19	Chang AS, Hathaway CK, Smithies O and Kakoki M: Transforming growth factor-β1 and diabetic nephropathy. Am J Physiol Renal Physiol. 310:F689–F696. 2016. View Article : Google Scholar : PubMed/NCBI
20	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
21	MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ and Jerums G: Normoalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care. 27:195–200. 2004. View Article : Google Scholar : PubMed/NCBI
22	Tsalamandris C, Allen TJ, Gilbert RE, Sinha A, Panagiotopoulos S, Cooper ME and Jerums G: Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes. 43:649–655. 1994. View Article : Google Scholar : PubMed/NCBI
23	Caramori ML, Kim Y, Huang C, Fish AJ, Rich SS, Miller ME, Russell G and Mauer M: Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes. Diabetes. 51:506–513. 2002. View Article : Google Scholar : PubMed/NCBI
24	Najafian B, Crosson JT, Kim Y and Mauer M: Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes. J Am Soc Nephrol. 17 Suppl 2:S53–S60. 2006. View Article : Google Scholar : PubMed/NCBI
25	Levey AS, Becker C and Inker LA: Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: A systematic review. JAMA. 313:837–846. 2015. View Article : Google Scholar : PubMed/NCBI
26	Glassock RJ: Is the presence of microalbuminuria a relevant marker of kidney disease? Curr Hypertens Rep. 12:364–368. 2010. View Article : Google Scholar : PubMed/NCBI
27	Stehouwer CDA and Smulders YM: Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. J Am Soc Nephrol. 17:2106–2111. 2006. View Article : Google Scholar : PubMed/NCBI
28	Silva AM, Schaan BD, Signori LU, Plentz RD, Moreno H Jr, Bertoluci MC and Irigoyen MC: Microalbuminuria is associated with impaired arterial and venous endothelium dependent vasodilation in patients with type 2 diabetes. J Endocrinol Invest. 33:696–700. 2010. View Article : Google Scholar : PubMed/NCBI
29	Suarez Gonzalez 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. View Article : Google Scholar : PubMed/NCBI
30	Alter ML, Kretschmer A, Von Websky K, Tsuprykov O, Reichetzeder C, Simon A, Stasch JP and Hocher B: Early urinary and plasma biomarkers for experimental diabetic nephropathy. Clin Lab. 58:659–671. 2012.PubMed/NCBI
31	Kato M and Natarajan R: MicroRNAs in diabetic nephropathy: Functions, biomarkers, and therapeutic targets. Ann N Y Acad Sci. 1353:72–88. 2015. View Article : Google Scholar : PubMed/NCBI
32	Wang Q, Wang Y, Minto AW, Wang J, Shi Q, Li X and Quigg RJ: MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 22:4126–4135. 2008. View Article : Google Scholar : PubMed/NCBI
33	Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi J and Natarajan R: MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci USA. 104:93432–3437. 2007. View Article : Google Scholar
34	Yang Y, Xiao L, Li J, Kanwar YS, Liu F and Sun L: Urine miRNAs: Potential biomarkers for monitoring progression of early stages of diabetic nephropathy. Med Hypotheses. 81:274–278. 2013. View Article : Google Scholar : PubMed/NCBI
35	Simpson K, Wonnacott A, Fraser DJ and Bowen T: MicroRNAs in diabetic nephropathy: From biomarkers to therapy. Curr Diab Rep. 16:352016. View Article : Google Scholar : PubMed/NCBI
36	Al-Kafaji G, Al-Mahroos G, Al-Muhtaresh HA, Skrypnyk C, Sabry MA and Ramadan AR: Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker. Exp Ther Med. 12:815–822. 2016. View Article : Google Scholar : PubMed/NCBI
37	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
38	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
39	Lutale JJ, Thordarson H, Abbas ZG and Vetvik K: Microalbuminuria among type 1 and type 2 diabetic patients of African origin in Dar Es Salaam, Tanzania. BMC Nephrol. 8:22007. View Article : Google Scholar : PubMed/NCBI
40	Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH and Krolewski AS: Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 348:2285–2293. 2003. View Article : Google Scholar : PubMed/NCBI
41	Rossing P, Hougaard P and Parving HH: Progression of microalbuminuria in type 1 diabetes: Ten-year prospective observational study. Kidney Int. 68:1446–1450. 2005. View Article : Google Scholar : PubMed/NCBI
42	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
43	Keller A, Leidinger P, Bauer A, Elsharawy A, Haas J, Backes C, Wendschlag A, Giese N, Tjaden C, Werner J, et al: Toward the blood-borne miRNome of human diseases. Nat Methods. 8:841–843. 2011. View Article : Google Scholar : PubMed/NCBI
44	Ma X, Lu C, Lv C, Wu C and Wang Q: The expression of miR-192 and its significance in diabetic nephropathy patients with different urine albumin creatinine ratio. J Diabetes Res. 2016:67894022016. View Article : Google Scholar : PubMed/NCBI
45	Chien HY, Chen CY, Chiu YH, Lin YC and Li WC: Differential microRNA profiles predict diabetic nephropathy progression in Taiwan. Int J Med Sci. 13:457–465. 2016. View Article : Google Scholar : PubMed/NCBI
46	Tian Z, Greene AS, Pietrusz JL, Matus IR and Liang M: MicroRNA-target pairs in the rat kidney identified by microRNA microarray, proteomic, and bioinformatic analysis. Genome Res. 18:404–411. 2008. View Article : Google Scholar : PubMed/NCBI
47	Sun Y, Koo S, White N, Peralta E, Esau C, Dean NM and Perera RJ: Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs. Nucleic Acids Res. 32:e1882004. View Article : Google Scholar : PubMed/NCBI
48	Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A and Fraser D: Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol. 21:438–447. 2010. View Article : Google Scholar : PubMed/NCBI
49	Wang B, Herman-Edelstein M, Koh P, Burns W, Jandeleit-Dahm K, Watson A, Saleem M, Goodall GJ, Twigg SM, Cooper ME and Kantharidis P: E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-β. Diabetes. 59:1794–1802. 2010. View Article : Google Scholar : PubMed/NCBI
50	Putta S, Lanting L, Sun G, Lawson G, Kato M and Natarajan R: Inhibiting MicroRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J Am Soc Nephrol. 23:458–469. 2012. View Article : Google Scholar : PubMed/NCBI
51	Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML and Zelmanovitz T: Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care. 28:164–176. 2005. View Article : Google Scholar : PubMed/NCBI
52	Al-Rubeaan K, Youssef AM, Subhani SN, Ahmad NA, Al-Sharqawi AH, Al-Mutlaq HM, David SK and AlNaqeb D: Diabetic nephropathy and its risk factors in a society with a type 2 diabetes epidemic: A Saudi National Diabetes Registry-based study. PLoS One. 9:e889562014. View Article : Google Scholar : PubMed/NCBI
53	Jia Y, Guan M, Zheng Z, Zhang Q, Tang C, Xu W, Xiao Z, Wang L and Xue Y: miRNAs in urine extracellular vesicles as predictors of early-stage diabetic nephropathy. J Diabetes Res. 2016:79327652016. View Article : Google Scholar : PubMed/NCBI