Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke

Abstract

Purpose of review: Remarkable progress has been achieved over the past 2 years in understanding the cellular actions of renalase, its pathophysiology and potential therapeutic utility.

Recent findings: There has been a paradigm shift in our thinking about the mechanisms underlying the cellular actions of renalase. We now understand that, independent of its enzymatic properties, renalase functions as a signaling molecule, a cytokine that interacts with a yet-to-be identified plasma membrane receptor(s) to activate protein kinase B and the mitogen-activated protein kinase pathway. These signaling properties are critical to its cytoprotective effects. New information regarding renalase's enzymatic function as an α-nicotinamide adenine dinucleotide oxidase/anomerase will be reviewed. Lastly, we will discuss the association of certain single nucleotide polymorphisms in the renalase gene with type 1 diabetes and with ischemic stroke, and the clinical implications of these findings.

Summary: The consistent association of renalase single nucleotide polymorphisms and the development of type 1 diabetes is a great interest particularly because we now understand that renalase functions as a cytokine. Future work on renalase should focus on exploring the identity of its receptor(s), and its potential role as an immune modulator.

FIGURE 1

Time course of renalase-dependent cell signaling. Human embryonic kidney cells (HK-2) incubated with renalase and activation of protein kinase B (AKT) and extracellular-signal regulated kinase (ERK) determined by Western blot analysis; representative blot is shown (n=3); signals normalized to glyceraldehyde 3-phosphate dehydrogenase loading control (n=3); changes over baseline statistically significant at from 1 to 60 min for ERK, and AKT (T308) and at 30 min only for AKT (S473).

FIGURE 2

Renalase isoforms Ren1–7: exons numbered from 1 to 10. RP-224, renalase peptide amino acid 224 233 of Ren1 or Ren2; RP-220, amino acids 220–239; RP-H220, histidine-tagged RP- 220; RP-Scr220, scrambled RP-220.

FIGURE 3

Extracellular signal-regulated kinase or activation of protein kinase B inhibition abrogates protective effect of renalase peptide. Wild-type mice subjected to sham surgery or to 30 min of renal ischemia and reperfusion; RP-H220 or vehicle (saline) injected 10 min before renal ischemia. Extracellular signal-regulated kinase inhibitor PD98059 or the PI3K or activation of protein kinase B inhibitor wortmannin abrogated RP-H220’s protective effect.

FIGURE 4

Renalase and α-NAD(P)H oxidase/anomerase: proposed scheme. Oxidation of α-dihydropyridyl ring of NAD(P), with transfer of two electrons to the flavin cofactor of renalase, and conversion of the ribose C1 from α to β configuration; reduced FAD cofactor is reoxidized by reacting with dioxygen-yielding hydrogen peroxide as a reaction byproduct.

FIGURE 5

Working model of renalase as a cytokine. Extracellular renalase interacts with a plasma membrane receptor to activate protein kinase B and extracellular signal-regulated kinase and increase cell survival.