Date of Award

January 2019

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Fred S. Gorelick

Abstract

Renalase (RNLS) is a serum protein secreted by the kidney and other tissues that has been found to be protective in acute injury in the kidney and heart. In addition, it has been shown that renalase appears to disappear from serum during acute kidney injury. Given its apparent cytoprotective properties in other tissues, we hypothesized that renalase could have a protective role in acute pancreatitis (AP). We examined this using the cerulein hyperstimulation models of experimental AP. Using isolated murine pancreatic lobules, pretreatment with recombinant renalase (rRNLS) blocked trypsin activity induced by cerulein; when given as a therapeutic (after induction), rRNLS decreased morphologic and biochemical parameters of AP in vivo. A striking decrease in serum levels of endogenous renalase were observed within the first hour of cerulein pancreatitis. However, RNLS returned to levels at or higher than basal values during AP resolution. Because renalase seems to be acting as a cytokine or circulating growth factor, we hypothesized that, like other members of this functional group, it may bound to serum proteins. Size exclusion chromatography showed much of renalase is transported in serum in a high molecular weight complexes (>200 kDa) with masses greater than (37 kDa). Putative murine RNLS binding protein candidates were identified including murinoglobulin and pregnancy zone protein, which are members of the alpha-2 macroglobulin domain family. Finally, we observed that levels both renalase and its potential binding proteins dramatically increase in the kidney as renalase levels in the serum decreases during AP onset, suggesting that select tissue sequestration may modulate serum RNLS during disease. This decrease in serum renalase may help explain the benefit of exogenous RNLS as an AP treatment.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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