The serum protein renalase reduces injury in experimental pancreatitis

Abstract

Acute pancreatitis is a disease associated with inflammation and tissue damage. One protein that protects against acute injury, including ischemic injury to both the kidney and heart, is renalase, which is secreted into the blood by the kidney and other tissues. However, whether renalase reduces acute injury associated with pancreatitis is unknown. Here, we used both and murine models of acute pancreatitis to study renalase's effects on this condition. In isolated pancreatic lobules, pretreatment with recombinant human renalase (rRNLS) blocked zymogen activation caused by cerulein, carbachol, and a bile acid. Renalase also blocked cerulein-induced cell injury and histological changes. In the cerulein model of pancreatitis, genetic deletion of renalase resulted in more severe disease, andadministering rRNLS to cerulein-exposed WT mice after pancreatitis onset was protective. Because pathological increases in acinar cell cytosolic calcium levels are central to the initiation of acute pancreatitis, we also investigated whether rRNLS could function through its binding protein, plasma membrane calcium ATPase 4b (PMCA4b), which excretes calcium from cells. We found that PMCA4b is expressed in both murine and human acinar cells and that a PMCA4b-selective inhibitor worsens pancreatitis-induced injury and blocks the protective effects of rRNLS. These findings suggest that renalase is a protective plasma protein that reduces acinar cell injury through a plasma membrane calcium ATPase. Because exogenous rRNLS reduces the severity of acute pancreatitis, it has potential as a therapeutic agent.

Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes

“…Of note, RNLS may have enzyme-independent properties as an extracellular receptor ligand in other tissues 38 , 39 . The RNLS protein was reported to be protective in this role 40 that seems to be distinct from the enzymatic function underlying the results presented here.…”

Decreased plasma levels of the survival factor renalase are associated with worse outcomes in COVID-19

“…This finding corresponds with studies showing the anti-inflammatory properties of RNLS. 3,4 Low RNLS levels may therefore be associated with increased inflammation and more severe COVID19 disease. To our knowledge, this is the first study to report an association between plasma RNLS levels and COVID-19 severity.…”

“…Renalase (RNLS), a protein highly expressed in kidney and secreted into blood, displays potent prosurvival and anti-inflammatory effects. In acute kidney injury, 3 and acute pancreatitis, 4 reduced blood RNLS leads to increased organ injury and inflammation. Cellular injury, disordered inflammatory responses, increased inflammasome-driven pathways and reduced T-cell function together are central to the pathogenesis of COVID-19.…”

Elevated renalase levels in patients with acute coronary microvascular dysfunction – A possible biomarker for ischemia

“…Human recombinant RNLS (hrRNLS) was used as the calibrator and synthesized as previously described (detailed protocol in Appendix B). 22 We generated the capture monoclonal antibody (m42-RNLS) using a previously described method. 23 The detection antibody is a commercially available goat polyclonal renalase antibody (Abcam, ab31291), generated using an unrelated peptide to that used for m42-RNLS.…”