Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4.

VENTIMIGLIA MARIA SILVIA; NAJENSON ANA CLARA; PERAZZO JC; CAROZZO ALEJANDRO; MARCELO VATTA; DAVIO CARLOS; BIANCIOTTI, LILIANA

MOLECULAR MEDICINE

FEINSTEIN INST MED RES

Año: 2015 vol. 21 p. 58 - 67

1076-1551

We previously reported that atrial natriuretic factor (ANF) stimulates secretin-evoked cAMP efflux through multidrug resistanceassociatedprotein 4 (MRP4) in the exocrine pancreas. Here we sought to establish in vivo whether this mechanism was involvedin acute pancreatitis onset in the rat. Rats pretreated with or without probenecid (MRPs general inhibitor) were infused with secretinalone or with ANF. A set of these animals were given repetitive cerulein injections to induce acute pancreatitis. Plasma amylaseand intrapancreatic trypsin activities were measured and histological examination of the pancreas performed. Secretinalone activated trypsinogen but induced no pancreatic histological changes. Blockade by probenecid in secretin-treated ratsincreased trypsin and also induced vacuolization, a hallmark of acute pancreatitis. ANF prevented the secretin response but inthe absence of probenecid. In rats with acute pancreatitis, pretreatment with secretin aggravated the disease, but ANF preventedsecretin-induced changes. Blockade of MRPs in rats with acute pancreatitis induced trypsinogen activation and largercytoplasmic vacuoles as well as larger areas of necrosis and edema that were aggravated by secretin but not prevented by ANF.The temporal resolution of intracellular cAMP levels seems critical in the onset of acute pancreatitis, since secretin-evoked cAMPin a context of MRP inhibition makes the pancreas prone to injury in normal rats and aggravates the onset of acute pancreatitis.Present findings support a protective role for ANF mediated by cAMP extrusion through MRP4 and further suggest that the regulationof MRP4 by ANF would be relevant to maintain pancreatic acinar cell homeostasis.