Extracellular renalase protects cells and organs by outside-in signalling

Abstract

Renalase was discovered as a protein synthesized by the kidney and secreted in blood where it circulates at a concentration of approximately 3-5 μg/ml. Initial reports suggested that it functioned as an NAD(P)H oxidase and could oxidize catecholamines. Administration of renalase lowers blood pressure and heart rate and also protects cells and organs against ischaemic and toxic injury. Although renalase's protective effect was initially ascribed to its oxidase properties, a paradigm shift in our understanding of the cellular actions of renalase is underway. We now understand that, independent of its enzymatic properties, renalase functions as a cytokine that provides protection to cells, tissues and organs by interacting with its receptor to activate protein kinase B, JAK/STAT, and the mitogen-activated protein kinase pathways. In addition, recent studies suggest that dysregulated renalase signalling may promote survival of several tumour cells due to its capacity to augment expression of growth-related genes. In this review, we focus on the cytoprotective actions of renalase and its capacity to sustain cancer cell growth and also the translational opportunities these findings represent for the development of novel therapeutic strategies for organ injury and cancer.

Keywords: cell signalling; immune-oncology; ischaemic injury; macrophages; renalase; survival factor.

Figure 1

Working model of renalase as a cytokine. Extracellular renalase interacts with a plasma membrane receptor to activate signal transducer and activator of transcription (STAT3) and mitogen‐activated protein kinase (MAPK) pathways and increase cell survival. PMCA4b: plasma membrane calcium ATPase isoform 4b, AKT: protein kinase B, ERK: extracellular signal‐regulated kinase, p38: p38 mitogen‐activated kinase.

Figure 2

Proposed mechanism of action of m28‐RNLS. Inhibition of renalase signalling decreases renalase secretion from CD163+ TAMs and inhibits RNLS signalling in melanoma cells, all leading to a significant increase in p21 and reduction in MAPK pathways, and cellular apoptosis. m28‐RNLS: antirenalase monoclonal antibody, PMCA4b: plasma membrane calcium ATPase isoform 4b, STAT3: signal transducer and activator of transcription, AKT: protein kinase B, ERK: extracellular signal‐regulated kinase, p38: p38 mitogen‐activated kinase.