This proposal will continue the topic of our current Merit Award and examine a relatively recently described secretory protein, renalase, which appears to have a potent and novel protective role in acute pancreatitis (AP). AP has an incidence of up to 5/10,000 in the U.S. population, but is much more common in Veterans. It can cause death in 30% of those with severe disease, and is the most common reason for hospitalization for individuals with gastrointestinal disease in the U.S. Since AP is often caused by alcohol abuse, cigarette smoking, and increases in incidence with age, it is frequently encountered in our Veteran population. During this funding period we published a manuscript that examined most of our current Merit Aims on renalase in experimental murine AP and showed that: 1) Plasma renalase levels fell dramatically at the onset of AP and rebounded much higher than basal levels during recovery, 2) Genetic deletion of renalase was associated with worse experimental AP, 3) Administering recombinant renalase (rRNLS) reduced experimental AP severity in vivo even when given after disease onset, 4) rRNLS could act directly on pancreatic acinar cells to reduce injury, 5) The protective effects of renalase on acinar cells is mediated by a specific plasma-membrane calcium export pump (PMCA4b). Our preliminary studies in clinical AP suggest that plasma renalase levels also falls in human AP and may reflect disease severity. Here we propose to extend these observations with 3 specific aims that will examine the following questions: 1) Does renalase also affect recovery from acute pancreatitis? 2) What mechanisms account for the rapid decrease in plasma renalase and appearance in the kidney in experimental AP and the subsequent increases in plasma renalase during recovery? 3) Do plasma binding proteins interact with RNLS and how might it affect its biology? These issues are relevant when considering renalase as a potential AP therapy because the data could serve as a guide for its future administration by showing benefits when given well after disease onset to promote recovery. The plasma levels of renalase may be a prognostic factor for AP severity and could also guide therapies including administering renalase. The following preliminary data provides a scientific foundation for pursuing these questions and aims. First, we find that severe human AP is associated with levels of plasma renalase that are persistently lower than baseline, indicating a deficient. We propose to examine the levels of plasma renalase in other murine AP models, including one that causes severe disease, to determine whether they conform to the patterns in human. In mice with genetic deletion of renalase, we find that AP recovery is delayed. The human and AP model findings led us to predict that renalase may be act to both reduce the acute AP severity and enhance recovery- we will test this experimentally. Second, we observe that during AP, the levels of renalase in the kidney dramatically increase in the mouse kidney while the plasma levels reach their nadir; kidney renalase mRNA levels fall during this time, suggesting the absence of new kidney renalase synthesis. We conclude the acute kidney increase is likely due to sequestration. We also find that plasma renalase levels rebound well above baseline during experimental AP recovery. We propose to explore these responses by examining plasma renalase trafficking and turnover. The potential uptake and secretion by the kidney during AP onset and the source(s) of plasma renalase during AP recovery will also be examined. Third, we find that a major fraction of plasma renalase is bound to alpha-2-macroglobulin family proteins in murine plasma and predict that humans will be similar. We propose to explore the trafficking of these proteins during AP and their interactions with renalase. We believe that these studies in murine models should provide useful insights for future studies of renalase in clinical pancreatitis including its most appropriate potential uses as a as a therapeutic agent.
Acute pancreatitis, an inflammatory disease of the pancreas, is severe in about 25% of patients and causes death in up to 30% of those with severe disease; there is no specific therapy. The most common causes of acute pancreatitis are alcohol abuse, cigarette smoking and gallstones. Since these conditions are more common in our Veterans, the proposed work has strong clinical relevance. Using animal and cellular model of pancreatitis, we have discovered a blood protein (renalase) that protects against pancreatitis, but tends to disappear from blood early in disease. We propose to study renalase for two reasons: 1) It appears to have a strong protective role in pancreatitis and could represent a new therapy, 2) Blood levels of renalase might predict which patients will develop severe disease and also benefit from its use as a therapy.
|Kolodecik, Thomas R; Reed, Anamika M; Date, Kimie et al. (2017) The serum protein renalase reduces injury in experimental pancreatitis. J Biol Chem 292:21047-21059|
|Gorelick, Fred S; Lerch, Markus M (2017) Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Cell Mol Gastroenterol Hepatol 4:251-262|
|Srinivasan, Padmanabhan; Thrower, Edwin C; Gorelick, Fred S et al. (2016) Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Am J Physiol Gastrointest Liver Physiol 310:G874-83|
|Gorelick, Fred S (2016) Advances in pancreatology: 2016. Curr Opin Gastroenterol :|
|Guo, Xiaojia; Hollander, Lindsay; MacPherson, Douglas et al. (2016) Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer. Sci Rep 6:22996|
|Chung, Chuhan; Gorelick, Fred S (2016) Targeting ?v Integrins in Pancreatic Fibrosis: Progress in Resolving the Scar. Cell Mol Gastroenterol Hepatol 2:405-406|