title: MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury.
abstract: Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and microRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-β, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes.
authors.affiliation: School of Science and Technology, Federation University Australia, Ballarat, Victoria, Australia; and.
authors.forename: Indrajeetsinh
authors.initials: I
authors.lastname: Rana
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: Velkoska
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Patel
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
authors.affiliation: School of Science and Technology, Federation University Australia, Ballarat, Victoria, Australia; and f.charchar@federation.edu.au.
authors.forename: Fadi J
authors.initials: FJ
authors.lastname: Charchar
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress / Q000187:drug effects; D017257:Ramipril / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D051017:Apoptosis Regulatory Proteins; C548821:MIRN132 microRNA, rat; C549446:MIRN133 microRNA, rat; C552427:MIRN212 microRNA, rat; D035683:MicroRNAs; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D003094:Collagen; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D017257:Ramipril
keywords: angiotensin-converting enzyme inhibitors; cardiorenal cross talk; microRNA; microRNA-1; microRNA-133; microRNA-212/132; subtotal nephrectomy