Renalase Prevents AKI Independent of Amine Oxidase Activity

J Am Soc Nephrol. 2014 Jun;25(6):1226-35. doi: 10.1681/ASN.2013060665. Epub 2014 Feb 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Amine Oxidase (Copper-Containing) / metabolism
  • Animals
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Line
  • Cisplatin / toxicity
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / enzymology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase / pharmacology*
  • Oxidants / toxicity
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology

Substances

  • Antineoplastic Agents
  • Oxidants
  • Recombinant Proteins
  • Amine Oxidase (Copper-Containing)
  • Monoamine Oxidase
  • renalase
  • AKT1 protein, human
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Cisplatin