TY - JOUR
T1 - Post-Transcriptional Regulation of Renalase Gene by MIR-29 and MIR-146 MicroRNAs
T2 - Implications for Cardiometabolic Disorders
AU - Kalyani, Ananthamohan
AU - Sonawane, Parshuram J.
AU - Khan, Abrar Ali
AU - Subramanian, Lakshmi
AU - Ehret, Georg B.
AU - Mullasari, Ajit S.
AU - Mahapatra, Nitish R.
N1 - Funding Information:
Authors thank Prof. D. Karunagaran and Dr. M. Subramanian, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, for kindly providing them with miR-29 expression plasmids; Mark Boldin, Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, for the miR-146b expression plasmid; and Anindya Dutta, Department of Biochemistry and Molecular Genetics Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, for the miR-378 expression plasmid. Authors also thank ICBP for their contribution to blood pressure data, MAGIC investigators for their contributions to glycemic traits data and investigators of GWAS for total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides for their contributions to lipid traits data. A.K. is thankful to the Council of Scientific and Industrial Research, Government of India, for research fellowship. This work was supported by a grant ( BT/PR4928/AGR/36/713/2012 ) from the Department of Biotechnology, Government of India to N.R.M.
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/8/14
Y1 - 2015/8/14
N2 - Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3′-UTR (untranslated region) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (∼ 1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (∼ 2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3′-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3′-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations (n ≈ 58,000-96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits.
AB - Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3′-UTR (untranslated region) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (∼ 1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (∼ 2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3′-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3′-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations (n ≈ 58,000-96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits.
KW - cardiometabolic traits
KW - microRNA
KW - post-transcriptional
KW - renalase
KW - single nucleotide polymorphism
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U2 - 10.1016/j.jmb.2015.07.003
DO - 10.1016/j.jmb.2015.07.003
M3 - Article
C2 - 26165231
AN - SCOPUS:84938201505
SN - 0022-2836
VL - 427
SP - 2629
EP - 2646
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 16
ER -