title: Renalase deficiency aggravates ischemic myocardial damage.
abstract: Chronic kidney disease (CKD) leads to an 18-fold increase in cardiovascular complications not fully explained by traditional risk factors. Levels of renalase, a recently discovered oxidase that metabolizes catecholamines, are decreased in CKD. Here we show that renalase deficiency in a mouse knockout model causes increased plasma catecholamine levels and hypertension. Plasma blood urea nitrogen, creatinine, and aldosterone were unaffected. However, knockout mice had normal systolic function and mild ventricular hypertrophy but tolerated cardiac ischemia poorly and developed myocardial necrosis threefold more severe than that found in wild-type mice. Treatment with recombinant renalase completely rescued the cardiac phenotype. To gain insight into the mechanisms mediating this cardioprotective effect, we tested if gene deletion affected nitrate and glutathione metabolism, but found no differences between hearts of knockout and wild-type mice. The ratio of oxidized (NAD) to reduced (NADH) nicotinamide adenine dinucleotide in cardiac tissue, however, was significantly decreased in the hearts of renalase knockout mice, as was plasma NADH oxidase activity. In vitro studies confirmed that renalase metabolizes NADH and catecholamines. Thus, renalase plays an important role in cardiovascular pathology and its replacement may reduce cardiac complications in renalase-deficient states such as CKD.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8029, USA.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wu
authors.forename: Jianchao
authors.initials: J
authors.lastname: Xu
authors.forename: Heino
authors.initials: H
authors.lastname: Velazquez
authors.forename: Peili
authors.initials: P
authors.lastname: Wang
authors.forename: Guoyong
authors.initials: G
authors.lastname: Li
authors.forename: Dinggang
authors.initials: D
authors.lastname: Liu
authors.forename: Benedita
authors.initials: B
authors.lastname: Sampaio-Maia
authors.forename: Janete
authors.initials: J
authors.lastname: Quelhas-Santos
authors.forename: Kerry
authors.initials: K
authors.lastname: Russell
authors.forename: Raymond
authors.initials: R
authors.lastname: Russell
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Manuel
authors.initials: M
authors.lastname: Pestana
authors.forename: Frank
authors.initials: F
authors.lastname: Giordano
authors.forename: Gary V
authors.initials: GV
authors.lastname: Desir
mesh_terms: D000818:Animals; D001483:Base Sequence; D002316:Cardiotonic Agents / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy / Q000201:enzymology
chemical_list: D002316:Cardiotonic Agents; D017931:DNA Primers; D011994:Recombinant Proteins; D009243:NAD; D008995:Monoamine Oxidase; C521557:renalase; D009638:Norepinephrine; D004837:Epinephrine