Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Abstract

. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286: G784-G790, 2004. First published December 18, 2003 10.1152/ ajpgi.00446.2003.-CCK acts on pancreatic acinar cells to increase intracellular Ca 2ϩ leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/ threonine-specific protein phosphatase activated by Ca 2ϩ and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powdered diet with or without 0.1% camostat. Pancreatic wet weight, protein, and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice.cholecystokinin; camostat; FK506; cyclosporine A A VARIETY OF GASTROINTESTINAL peptides have been implicated in the regulation of proliferation and differentiation in the mature gastrointestinal tract and the pancreas (30,56). It is well known that feeding initiates pancreatic protein synthesis and secretion and that adaptation to a high-protein diet results in pancreatic growth (17, 18). More detailed studies have shown that among gastrointestinal peptides, CCK is released in response to dietary protein leading to pancreatic growth. Injection of CCK increases pancreatic wet weight and protein and DNA content in vivo over 4-10 days (8,37,40,43). Oral administration of soybean trypsin inhibitor (5, 44) or the synthetic protease inhibitor camostat (10,15,37,52,55), as well as pancreaticobiliary diversion (13, 39), increase the release of endogenous CCK into the blood and induce pancreatic growth. Moreover, CCK-A receptor antagonists that block the action of exogenous and endogenous CCK inhibit pancreatic growth (10, 13, 37, 39, 52). Therefore, most of the studies of pancreatic growth have been focused on CCK as a key regulator.In pancreatic acinar cells, the intracellular mechanisms of enzyme secretion have been well documented. CCK activates the release of intracellular Ca 2ϩ and the influx of Ca 2ϩ and generate...

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

“…Its endogenous counterpart, CCK, is elevated in the blood after a meal high in fats or proteins (20). Inhibition of gut trypsin activity also increases CCK release from intestinal endocrine cells by activating trypsin feedback regulation of CCK release (21)(22)(23). Camostat is a common trypsin inhibitor that has been widely used experimentally to increase circulating endogenous CCK.…”

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

“…Methylene blue dye was added to trace the path of the solution. Mice were sacrificed after 30 minutes, and blood was collected for CCK measurement using the CCK bioassay method (21). Ildr1 -/-and wild-type mice used in these experiments were obtained by breeding of heterozygous mice.…”

Regulation of Normal and Adaptive Pancreatic Growth

“…Until recently the most common technique was dissecting and weighing the pancreas. This yields values for young adults, usually males, fed a control diet, of 8-12 mg pancreatic weight/g body weight for mice (22,64,120,125,143), 22.5 mg PW/gBW for Syrian Hamster (124), 2.5-4 mg PW/g BW for rats (25,34,40,57,123,158), and 0.5-1.1 g PW/kg BW for adult humans (13,127). Note that the relative pancreas size gets smaller as the animal gets larger.…”

“…In rats the action of CCK was shown to be directly on acinar cells (158). In mice the effect of TI is not seen following the genetic deletion of either CCK or the CCK receptor (64,125,143). In both rats and mice the adaptive growth is reversible and when the TI is removed the pancreas returns to its original size (21, 105,106).…”

“…CCK is known to activate a number of signaling pathways but a central role has been assigned to activation of intracellular Ca necessary for TI stimulated pancreatic growth that occurs by activation of mitogenesis (143). A major target of CN are NFATs (Nuclear Factor of Activated T Cells).…”