Correlation between serum miR-154-5p and urinary albumin excretion rates in patients with type 2 diabetes mellitus: a cross-sectional cohort study

Abstract

This study aimed to investigate the correlation between serum miR-154-5p and urinary albumin to creatinine ratio (UACR) in patients with type 2 diabetes mellitus (T2DM) and the association with biomarkers of inflammation and fibrosis in diabetic kidney disease (DKD). A total of 390 patients with T2DM were divided into three groups: normal albuminuria (UACR<30 mg/g, n=136, NA), microalbuminuria (UACR at 30–300 mg/g, n=132, MA), and clinical albuminuria (UACR>300 mg/g, n=122, CA). Circulating miR-154-5p, inflammatory (C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); and tumor necrosis factor-α (TNF-α) and fibrotic markers (vascular endothelial growth factor (VEGF); transforming growth factor-β1 (TGF-β1); and fibronectin (FN)), and other biochemical indicators were assessed via real-time PCR, enzyme-linked immunosorbent assay, and chemiluminescence assay in patients with T2DM and 138 control subjects (NC). UACR, miR-154-5p, glycated hemoglobin (HbA1c), serum creatinine (sCr), blood urea nitrogen (BUN), ESR, CRP, VEGF, TNF-α, TGF-β1, and FN were significantly higher and the estimated glomerular filtration rate (eGFR) was significantly lower in NA, MA, and CA groups than in NC subjects (P<0.05). Elevated levels of UACR and miR-154-5p were directly correlated with HbA1c, sCr, BUN, ESR, CRP, VEGF, TNF-α, TGF-β1, and FN and negatively correlated with eGFR (P<0.05). miR-154-5p, HbA1c, sCr, BUN, eGFR, ESR, CRP, VEGF, TNF-α, TGF-β1, and FN were important factors affecting UACR. These findings indicated that elevated serum miR-154-5p is significantly correlated with high UACR in patients with T2DM and may offer a novel reference for the early diagnosis of DKD.

Keywords

type 2 diabetes mellitus / diabetic kidney disease / miR-154-5p / urinary albumin to creatinine ratio

References

[1] Sandeep V. Type 2 diabetes. Ann Intern Med 2015; 162(5): 231–242

[2] Quiroga B, Arroyo D, de Arriba G. Present and future in the treatment of diabetic kidney disease. J Diabetes Res 2015; 2015: 801348

[3] Toth-Manikowski S, Atta MG. Diabetic kidney disease: pathophysiology and therapeutic targets. J Diabetes Res 2015; 2015: 697010

[4] Chamberlain JJ, Herman WH, Leal S, Rhinehart AS, Shubrook JH, Skolnik N, Kalyani RR. Pharmacologic therapy for type 2 diabetes: synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes. Ann Intern Med 2017; 166(8): 572–578

[5] Brownlee M, Aiello LP, Cooper ME, Vinik AI, Plutzky J, Boulton AJM. Chapter 33—Complications of Diabetes Mellitus. Elsevier Inc., 2016

[6] Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, Pasquinelli AE. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 2005; 122(4): 553–563

[7] Saito D, Maeshima Y, Nasu T, Yamasaki H, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis. Am J Physiol Renal Physiol 2011; 300(4): F873–F886

[8] Milosevic J, Pandit K, Magister M, Rabinovich E, Ellwanger DC, Yu G, Vuga LJ, Weksler B, Benos PV, Gibson KF, McMillan M, Kahn M, Kaminski N. Profibrotic role of miR-154 in pulmonary fibrosis. Am J Respir Cell Mol Biol 2012; 47(6): 879–887

[9] American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014; 37(Suppl 1): S14–S80

[10] Chalmers J. The 1999 WHO-ISH Guidelines for the Management of Hypertension. Med J Aust 1999; 171(9): 458–459

[11] Affara M, Sanders D, Araki H, Tamada Y, Dunmore BJ, Humphreys S, Imoto S, Savoie C, Miyano S, Kuhara S, Jeffries D, Print C, Charnock-Jones DS. Vasohibin-1 is identified as a master-regulator of endothelial cell apoptosis using gene network analysis. BMC Genomics 2013; 14(1): 23

[12] Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19): 2560–2572

[13] Yu R, Yang Y, Tian Y, Zhang Y, Lyu G, Zhu J, Xiao L, Zhu J. The mechanism played by 1,25-dihydroxyvitamin D3 in treating renal fibrosis in diabetic nephropathy. Chin J Endocrinol Metab (Zhonghua Nei Fen Mi Dai Xie Za Zhi) 2015; 9: 793–799 (in Chinese)

[14] Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3: 1–150

[15] Wang YC, Li Y, Wang XY, Zhang D, Zhang H, Wu Q, He YQ, Wang JY, Zhang L, Xia H, Yan J, Li X, Ying H. Circulating miR-130b mediates metabolic crosstalk between fat and muscle in overweight/obesity. Diabetologia 2013; 56(10): 2275–2285

[16] Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS, Sung JJ. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 2009; 58(10): 1375–1381

[17] Ortega FJ, Mercader JM, Moreno-Navarrete JM, Rovira O, Guerra E, Esteve E, Xifra G, Martínez C, Ricart W, Rieusset J, Rome S, Karczewska-Kupczewska M, Straczkowski M, Fernández-Real JM. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care 2014; 37(5): 1375–1383

[18] Shao Y, Ren H, Lv C, Ma X, Wu C, Wang Q. Changes of serum miR-217 and the correlation with the severity in type 2 diabetes patients with different stages of diabetic kidney disease. Endocrine 2017; 55(1): 130–138

[19] Ma X, Lu C, Lv C, Wu C, Wang Q. The expression of miR-192 and its significance in diabetic nephropathy patients with different urine albumin creatinine ratio. J Diabetes Res 2016; 2016: 6789402

[20] Lv C, Zhou YH, Wu C, Shao Y, Lu CL, Wang QY. The changes in miR-130b levels in human serum and the correlation with the severity of diabetic nephropathy. Diabetes Metab Res Rev 2015; 31(7): 717–724

[21] Lin X, Yang Z, Zhang P, Liu Y, Shao G. miR-154 inhibits migration and invasion of human non-small cell lung cancer by targeting ZEB2. Oncol Lett 2016; 12(1): 301–306

[22] Dambal S, Giangreco AA, Acosta AM, Fairchild A, Richards Z, Deaton R, Wagner D, Vieth R, Gann PH, Kajdacsy-Balla A, Van der Kwast T, Nonn L. MicroRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma. J Steroid Biochem Mol Biol 2017; 167: 192–202

[23] Luk JM, Burchard J, Zhang C, Liu AM, Wong KF, Shek FH, Lee NP, Fan ST, Poon RT, Ivanovska I, Philippar U, Cleary MA, Buser CA, Shaw PM, Lee CN, Tenen DG, Dai H, Mao M. DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival. J Biol Chem 2011; 286(35): 30706–30713

[24] Xin C, Zhang H, Liu Z. miR-154 suppresses colorectal cancer cell growth and motility by targeting TLR2. Mol Cell Biochem 2014; 387(1-2): 271–277

[25] Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA, Cairns MJ. Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry 2012; 17(8): 827–840

[26] Formosa A, Markert EK, Lena AM, Italiano D, Finazzi-Agro’ E, Levine AJ, Bernardini S, Garabadgiu AV, Melino G, Candi E. MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells. Oncogene 2014; 33(44): 5173–5182

[27] Seitz H, Royo H, Bortolin ML, Lin SP, Ferguson-Smith AC, Cavaillé J. A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Res 2004; 14(9): 1741–1748

[28] Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T, Andrew Lister T, Young BD, Debernardi S. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS One 2008; 3(5): e2141

[29] Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T, Margalit H. Clustering and conservation patterns of human microRNAs. Nucleic Acids Res 2005; 33(8): 2697–2706

[30] Kaminski N, Benos P, Corcoran D, Pandit KV, Milosevic J, Yousef H. MicroRNAs In Idiopathic Pulmonary Fibrosis. Mosby, Inc., 2012. 191–199

[31] Yang H, Wang L, Zhao J, Chen Y, Lei Z, Liu X, Xia W, Guo L, Zhang HT. TGF-b-activated SMAD3/4 complex transcriptionally upregulates N-cadherin expression in non-small cell lung cancer. Lung Cancer 2015; 87(3): 249–257

[32] Li Y, Hu F, Xue M, Jia YJ, Zheng ZJ, Wang L, Guan MP, Xue YM. Klotho down-regulates Egr-1 by inhibiting TGF-b1/Smad3 signaling in high glucose treated human mesangial cells. Biochem Biophys Res Commun 2017; 487(2): 216–222

[33] Huang J, Wu J, Li Y, Li X, Yang T, Yang Q, Jiang Y. Deregulation of serum microRNA expression is associated with cigarette smoking and lung cancer. BioMed Res Int 2014; 2014: 364316

[34] Zheng Y, Zhu C, Ma L, Shao P, Qin C, Li P, Cao Q, Ju X, Cheng G, Zhu Q, Gu X, Hua L. miRNA-154-5p inhibits proliferation, migration and invasion by targeting E2F5 in prostate cancer cell lines. Urol Int 2017; 98(1): 102–110

[35] Ding J, Li JL, Yu MK. Expression of miRNA-154 in astrocytomas and its clinical significance. Chin Clin Oncol (Lin Chuang Zhong Liu Xue Za Zhi) 2017; 22(4): 314–318 (in Chinese)

[36] Liu HY, Zhang CH. China’s urban and rural public health resources insufficiency input or unbalanced allocation. Chin Health Econ (Zhongguo Wei Sheng Jing Ji) 2012; 31(8): 12–15 (in Chinese)

[37] Feng Z. Chinese health care in rural areas. BMJ 2010; 341: c5254

[38] KDOQI. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic disease. Am J Kidney Dis 2007; 49(2 Suppl 2): S12–S154

[39] Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, Hirsch IB, Kalantar-Zadeh K, Narva AS, Navaneethan SD, Neumiller JJ, Patel UD, Ratner RE, Whaley-Connell AT, Molitch ME. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis 2014; 64(4): 510–533

[40] National Clinical Guideline Centre (UK). Chronic Kidney Disease (Partial Update): Early Identification and Management of Chronic Kidney Disease in Adults in Primary and Secondary Care. London: National Institute for Health and Care Excellence (UK). 2014

[41] Zitkus BS. Update on the American Diabetes Association Standards of Medical Care. Nurse Pract 2014; 39(8): 22–32

[42] Kanwar YS, Sun L, Xie P, Liu FY, Chen S. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol 2011; 6(1): 395–423

[43] Lan HY, Chung ACK. Transforming growth factor-b and Smads. Contrib Nephrol 2011; 170: 75–82

[44] Sato Y. The vasohibin family: a novel family for angiogenesis regulation. J Biochem 2013; 153(1): 5–11

[45] Yao XF, Cai D, Quan JJ. Levels and clinical significances of IGF-1, TGF-β and VEGF in patients with type 2 diabetic nephropathy. Med Pharm J Chin PLA (Jie Fang Jun Yi Yao Za Zhi) 2017; 29(6): 78–81 (in Chinese)

[46] Fathy SA, Mohamed MR, Ali M A M, El-Helaly AE, Alattar AT. Influence of IL-6, IL-10, IFN-γ and TNF-α genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients. Biomarkers 2019; 24(1): 43–55

[47] Lu C, Han HD, Mangala LS, Ali-Fehmi R, Newton CS, Ozbun L, Armaiz-Pena GN, Hu W, Stone RL, Munkarah A, Ravoori MK, Shahzad MM, Lee JW, Mora E, Langley RR, Carroll AR, Matsuo K, Spannuth WA, Schmandt R, Jennings NB, Goodman BW, Jaffe RB, Nick AM, Kim HS, Guven EO, Chen YH, Li LY, Hsu MC, Coleman RL, Calin GA, Denkbas EB, Lim JY, Lee JS, Kundra V, Birrer MJ, Hung MC, Lopez-Berestein G, Sood AK. Regulation of tumor angiogenesis by EZH2. Cancer Cell 2010; 18(2): 185–197

[48] Yeo ES, Hwang JY, Park JE, Choi YJ, Huh KB, Kim WY. Tumor necrosis factor (TNF-α) and C-reactive protein (CRP) are positively associated with the risk of chronic kidney disease in patients with type 2 diabetes. Yonsei Med J 2010; 51(4): 519–525

[49] Magri CJ, Calleja N, Buhagiar G, Fava S, Vassallo J. Factors associated with diabetic nephropathy in subjects with proliferative retinopathy. Int Urol Nephrol 2012; 44(1): 197–206

Acknowledgements

This study was supported by the Higher School “High-end Talent Team Construction” of Liaoning Province (No. [2014]187) and the Natural Science Foundation of Liaoning Province (No. 201602862), Liaoning Province, China.

Compliance with ethics guidelines

Huiwen Ren, Can Wu, Ying Shao, Shuang Liu, Yang Zhou, and Qiuyue Wang declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

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