title: Renalase prevents AKI independent of amine oxidase activity.
abstract: AKI is characterized by increased catecholamine levels and hypertension. Renalase, a secretory flavoprotein that oxidizes catecholamines, attenuates ischemic injury and the associated increase in catecholamine levels in mice. However, whether the amine oxidase activity of renalase is involved in preventing ischemic injury is debated. In this study, recombinant renalase protected human proximal tubular (HK-2) cells against cisplatin- and hydrogen peroxide-induced necrosis. Similarly, genetic depletion of renalase in mice (renalase knockout) exacerbated kidney injury in animals subjected to cisplatin-induced AKI. Interestingly, compared with the intact renalase protein, a 20-amino acid peptide (RP-220), which is conserved in all known renalase isoforms, but lacks detectable oxidase activity, was equally effective at protecting HK-2 cells against toxic injury and preventing ischemic injury in wild-type mice. Furthermore, in vitro treatment with RP-220 or recombinant renalase rapidly activated Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinases and downregulated c-Jun N-terminal kinase. In summary, renalase promotes cell survival and protects against renal injury in mice through the activation of intracellular signaling cascades, independent of its ability to metabolize catecholamines, and we have identified the region of renalase required for these effects. Renalase and related peptides show potential as therapeutic agents for the prevention and treatment of AKI.
authors: Department of Medicine, Veterans Affairs Connecticut Healthcare System, Yale University, New Haven, Connecticut; Renal Division, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;
authors: Ling
authors: L
authors: Wang
authors: Department of Medicine, Veterans Affairs Connecticut Healthcare System, Yale University, New Haven, Connecticut;
authors: Heino
authors: H
authors: Velazquez
authors: Department of Pathology, Yale University, New Haven, Connecticut; and.
authors: Gilbert
authors: G
authors: Moeckel
authors: Department of Medicine, Veterans Affairs Connecticut Healthcare System, Yale University, New Haven, Connecticut;
authors: John
authors: J
authors: Chang
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York.
authors: Ahrom
authors: A
authors: Ham
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York.
authors: H Thomas
authors: HT
authors: Lee
authors: Department of Medicine, Veterans Affairs Connecticut Healthcare System, Yale University, New Haven, Connecticut;
authors: Robert
authors: R
authors: Safirstein
authors: Department of Medicine, Veterans Affairs Connecticut Healthcare System, Yale University, New Haven, Connecticut; gary.desir@yale.edu.
authors: Gary V
authors: GV
authors: Desir
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000378:metabolism* / Q000494:pharmacology*; D016877:Oxidants / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016877:Oxidants; D011994:Recombinant Proteins; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase; C521557:renalase; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin