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  • The pancreatic acinar cell possesses

    2019-07-24

    The pancreatic acinar cell possesses abundant ER and exhibits the highest rate of protein synthesis as compared with other cell types. It is responsible for the synthesis, storage and release of a large number of digestive enzymes, necessary for the digestion and Oxaliplatin of nutrients. The acinar cell ER is normally prone to stress, but the cell has coping mechanisms to compensate it. Several studies show that key regulators of the UPR are significantly altered early during the course of AP [6,13]. We previously reported that atrial natriuretic peptide (ANP) significantly attenuates AP in the rat. ANP reduces plasma amylase activity, premature trypsinogen activation, acinar vacuolization and necrotic areas in cerulein-induced AP [14]. Furthermore, it significantly attenuates the inflammatory response by reducing NF-kB activation and proinflammatory cytokine generation as well as neutrophil infiltration [15]. We also reported that the atrial peptide negatively modulates intracellular cAMP levels evoked by secretin in acinar cells. It stimulates cAMP efflux through multidrug resistance-associated protein type 4 (MRP4) as a regulatory mechanism in addition to phosphodiesterase activity to restrict the intracellular accumulation of the cyclic nucleotide within the acinar cell to prevent cell damage [16,17]. In this sense, we reported that enhanced cAMP induced by secretin administration aggravates AP but pretreatment with ANP attenuates the severity of the disease [14]. These findings support a protective role for ANP in the exocrine pancreas to prevent acinar cell damage either in the presence of enhanced cAMP levels or in AP.
    Materials and methods
    Results
    Discussion The major finding of the present study is that ANP attenuates ER stress and stimulates ER stress-induced apoptosis in experimental AP. These findings correlate well with previous studies showing that ANP reduces the severity of AP in the rat [14,15]. Accumulation of misfolded and unfolded proteins in the ER induced by calcium depletion, oxidative stress or high cellular protein demand results in ER stress which triggers the UPR. This conserved cellular response is mediated by the activation of the ER resident proteins IRE1, ATF6 and PERK with the aim to restore ER homeostasis. The UPR mechanism clears misfolded proteins from ER, reduces the flow of proteins to the ER and enhances the expression of molecules tending to protect the cell. However, if the ER homeostasis is not restored, it leads to programmed cell death [9]. Increasing evidence shows that ER stress and altered UPR signaling are emerging as key contributors of the pathogenesis of various metabolic, neurodegenerative and inflammatory diseases [24]. Strong evidence supports that ER stress responses are involved in the early stages and progression of AP [6,25]. Early morphological changes in AP include swelling and vacuolization of the ER as well as loss of ribosomes. In this sense, key regulators of the ER stress response are significantly altered early during acute pancreatitis [13]. The components of the UPR are also involved in physiological processes like the development and differentiation of specialized secretory cells, the control of innate immunity, the control of energy metabolism and the synthesis of cholesterol and lipids. Silencing of genes encoding components of the UPR results in different outcomes [26]. The most serious is the ablation of XBP1 which triggers the collapse of the exocrine pancreas and salivary glands [27]. BiP is the major folding assisting chaperone and the primary controller of the UPR. Under normal conditions it binds to IRE1, PERK and ATF6 but under ER stress BiP dissociates from the stress sensor proteins to bind the unfolded proteins, so triggering the UPR. BiP level is highly sensitive to changes in ER status [4]. In the present study, BiP expression was increased in AP as previously reported, but pretreatment with ANP significantly diminished it, suggesting that ANP attenuates the UPR [4,28,29].