title: Post-Transcriptional Regulation of Renalase Gene by miR-29 and miR-146 MicroRNAs: Implications for Cardiometabolic Disorders.
abstract: 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.
authors.affiliation: Cardiovascular Genetics Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
authors.forename: Ananthamohan
authors.initials: A
authors.lastname: Kalyani
authors.affiliation: Cardiovascular Genetics Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
authors.forename: Parshuram J
authors.initials: PJ
authors.lastname: Sonawane
authors.affiliation: Cardiovascular Genetics Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
authors.forename: Abrar Ali
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Cardiovascular Genetics Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Subramanian
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.affiliation: Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai 600037, India.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Mullasari
authors.affiliation: Cardiovascular Genetics Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India. Electronic address: nmahapatra@iitm.ac.in.
authors.forename: Nitish R
authors.initials: NR
authors.lastname: Mahapatra
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002318:Cardiovascular Diseases / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics; D007022:Hypotension / Q000201:enzymology / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008995:Monoamine Oxidase / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D020413:3' Untranslated Regions; C542542:MIRN146 microRNA, human; C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D008995:Monoamine Oxidase; C521557:renalase
keywords: cardiometabolic traits; microRNA; post-transcriptional; renalase; single nucleotide polymorphism