Advertisement

Molecular Medicine

, Volume 21, Issue 1, pp 58–67 | Cite as

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

  • María Silvia Ventimiglia
  • Ana Clara Najenson
  • Juan Carlos Perazzo
  • Alejandro Carozzo
  • Marcelo S. Vatta
  • Carlos A. Davio
  • Liliana G. Bianciotti
Research Article

Abstract

We previously reported that atrial natriuretic factor (ANF) stimulates secretin-evoked cAMP efflux through multidrug resistance-associated protein 4 (MRP4) in the exocrine pancreas. Here we sought to establish in vivo whether this mechanism was involved in acute pancreatitis onset in the rat. Rats pretreated with or without probenecid (MRPs general inhibitor) were infused with secretin alone or with ANF. A set of these animals were given repetitive cerulein injections to induce acute pancreatitis. Plasma amylase and intrapancreatic trypsin activities were measured and histological examination of the pancreas performed. Secretin alone activated trypsinogen but induced no pancreatic histological changes. Blockade by probenecid in secretin-treated rats increased trypsin and also induced vacuolization, a hallmark of acute pancreatitis. ANF prevented the secretin response but in the absence of probenecid. In rats with acute pancreatitis, pretreatment with secretin aggravated the disease, but ANF prevented secretin-induced changes. Blockade of MRPs in rats with acute pancreatitis induced trypsinogen activation and larger cytoplasmic 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 cAMP in 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 regulation of MRP4 by ANF would be relevant to maintain pancreatic acinar cell homeostasis

Notes

Acknowledgments

The authors thank John A Williams (University of Michigan) for critical reading of the manuscript. Silvia Presmanes is also acknowledged for excellent technical assistance in histological studies. This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina (CONICET) (PIP-0370) and Agencia Nacional de Promociön Cientifica y Tecnológica (ANPCyT) (PICT2012-2755 and PICT2010-1571).

Supplementary material

10020_2015_2101058_MOESM1_ESM.pdf (13 mb)
Supplementary material, approximately 13.0 MB.

References

  1. 1.
    Gower WR Jr, et al. (2000) Regulation of atrial natriuretic peptide gene expression in gastric antum by fasting. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278:R770–80.CrossRefGoogle Scholar
  2. 2.
    Bianciotti LG, et al. (1998) Atrial natriuretic factor induced amylase output in the rat parotid gland appears to be mediated by the inositol phosphate pathway. Biochem. Biophys. Res. Commun. 247:123–28.CrossRefGoogle Scholar
  3. 3.
    Sabbatini ME, et al. (2003) Atrial natriuretic factor stimulates exocrine pancreatic secretion in the rat through NRP-C receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 285:G929–37.CrossRefGoogle Scholar
  4. 4.
    Ventimiglia MS, et al. (2008) Atrial natriuretic factor intracellular signaling in the rat submandibular gland. Regul. Pept. 150:43–9.CrossRefGoogle Scholar
  5. 5.
    Sabbatini ME, Vatta MS, Davio CA, Bianciotti LG. (2007) Atrial natriuretic factor negatively modulates secretin intracellular signaling in the exocrine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 292:G349–57.CrossRefGoogle Scholar
  6. 6.
    Rodriguez MR, et al. (2011) Atrial natriuretic factor stimulates the efflux of secretin-evoked cAMP in the exocrine pancreas through multidrug resistance proteins. Gastroenterology. 140:1292–302.CrossRefGoogle Scholar
  7. 7.
    Sassi Y, et al. (2008) Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation. J. Clin. Invest. 118:2747–57.CrossRefGoogle Scholar
  8. 8.
    Godinho RO, Costa VL. (2003) Regulation of intracellular cyclic AMP in skeletal muscle cells involves the efflux of cyclic nucleotide to the extracellular compartment. Br. J. Pharmacol. 138:995–1003.CrossRefGoogle Scholar
  9. 9.
    Copsel S, et al. (2011) Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J. Biol. Chem. 286:6979–88.CrossRefGoogle Scholar
  10. 10.
    Pattabiraman PP, Pecen PE, Rao PV. (2013) MRP4-mediated regulation of intracellular cAMP and cGMP levels in trabecular meshwork cells and homeostasis of intraocular pressure. Invest. Ophtalmol. Vis. Sci. 54:1636–49.CrossRefGoogle Scholar
  11. 11.
    Lu Z, Kolidecik TR, Karne S, Nyce M, Gorelick F. (2003). Effects of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini. Am. J. Physiol. Gastrointest. Liver Physiol. 85:G822–28.CrossRefGoogle Scholar
  12. 12.
    Perides G, et al. (2005) Secretin differentially sensitizes rat pancreatic acini to the effects of supramaximal stimulation with caerulein. Am. J. Physiol. Gastrointest. Liver Physiol. 289:G713–21.CrossRefGoogle Scholar
  13. 13.
    Sah RP, Garg P, Saluja AK. Pathogenic mechanisms of acute pancreatitis. (2012) Curr. Opin. Gastroenterol. 28:507–15.CrossRefGoogle Scholar
  14. 14.
    Mareninova OA, et al. (2009) Impaired authophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J. Clin. Invest. 119:3340–55.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Gukovsky I, Pandol SJ, Gukovskaya AS. (2012) Organellar dysfunction in the pathogenesis of pancreatitis. Antioxid. Redox Signal. 15:2699–710.CrossRefGoogle Scholar
  16. 16.
    Institute of Laboratory Animal Resources (U.S.), Committee on Care and Use of Laboratory Animals. (1985) Guide for the Care and Use of Laboratory Animals. Rev. 1985. Bethesda (MD): NIH. 83 pp. (NIH publication; no. 85-23).Google Scholar
  17. 17.
    Institute of Laboratory Animal Resources; Commission on Life Sciences; National Research Council. (1996) Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academy Press.Google Scholar
  18. 18.
    Williams JA, Kore M, Dormer RL. (1978) Actions of secretagogues on a new preparation of functionally intact isolated pancreatic acini. Am. J. Physiol. Endocrinol. Metab. 235:E517–24.CrossRefGoogle Scholar
  19. 19.
    Dembinski A, et al. (2006) Effect of ischemic preconditioning on pancreatic regeneration and pancreatic expression of vascular endothelial growth factor and platelet-derived growth factor-A in ischemia/reperfusion-induced pancreatitis. J. Physiol. Pharmacol. 57:39–58.PubMedGoogle Scholar
  20. 20.
    Seo SW, et al. (2007) Selective cyclooxygenase-2 inhibitor ameliorates cholecystokinin-octapeptideinduced acute pancreatitis in rats. World J. Gastroenterol. 19:2298–304.CrossRefGoogle Scholar
  21. 21.
    Davio CA, Cricco GP, Bergoc RM, Rivera E. (1995) H1 and H2 histamine receptors in NMU-induced carcinoma with atypical coupling to signal transducers. Biochem. Pharmacol. 50:91–6.CrossRefGoogle Scholar
  22. 22.
    van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG. (2002) The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol. 13:595–603.PubMedGoogle Scholar
  23. 23.
    Sinha C, et al. (2013) Multi-drug resistance protein 4 (MRP4)-mediated regulation of fibroblast cell migration reflects a dichotomous role of intracellular cyclic nucleotides. J. Biol. Chem. 288:3786–94.CrossRefGoogle Scholar
  24. 24.
    Keppler D. (2011) Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Handb Exp Pharmacol. 201:299–323.CrossRefGoogle Scholar
  25. 25.
    Russel FG, Koenderink JB, Masereeuw R. (2008) Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signaling molecules. Trends Pharmacol. Sci. 29:200–7.CrossRefGoogle Scholar
  26. 26.
    Konig J, et al. (2005) Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int. J. Cancer. 115:359–67.CrossRefGoogle Scholar
  27. 27.
    Chaudburi A, Kolodecik TR, Gorelick FS. (2005) Effects of increased intracellular cAMP on carbachol stimulated zymogen activation, secretion and injury in the pancreatic acinar cell. Am. J. Physiol. Gastrointest. Liver Physiol. 288:G235–43.CrossRefGoogle Scholar
  28. 28.
    Renner IG, Wisner Jr, Lavigne BC. (1986) Partial restoration of pancreatic function by exogenous secretin in rats with ceruletide-induced acute pancreatitis. Dig. Dis. Sci. 31:305–13.CrossRefGoogle Scholar
  29. 29.
    Renner IG, Wisner JR Jr, Rinderknecht H. (1983) Protective effects of exogenous secretin on ceruletide-induced acute pancreatitis in the rat. J. Clin. Invest. 72:1081–92.CrossRefGoogle Scholar
  30. 30.
    Renner IG, Wisner JR Jr. (1986) Ceruletide-induced acute pancreatitis in the dog and its amelioration of exogenous secretin. Int. J. Pancreatol. 1:39–49.PubMedGoogle Scholar
  31. 31.
    Niederau C, Ferrell LD, Grendell JH. (1985) Caerulein-induced acute necrotizing pancreatitis in mice: protective effects of proglumide, benzotript, and secretin. Gastroenterology. 88:1192–204.CrossRefGoogle Scholar
  32. 32.
    Pallagi P, et al. (2014) The role of pancreatic ductal secretion in protection against acute pancreatitis in mice. Crit. Care Med. 42:177–88.CrossRefGoogle Scholar
  33. 33.
    Bhatia M. Apoptosis versus necrosis in acute pancreatitis. (2004) Am. J. Physiol. Gastrointest. Liver Physiol. 286:G189–96.CrossRefGoogle Scholar
  34. 34.
    Wu CF, Bishopric NH, Pratt RE. (1997) Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J. Biol. Chem. 272:14860–66.CrossRefGoogle Scholar
  35. 35.
    Ethridge RT, et al. (2002) Cyclooxygenase-2 gene disruption attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury. Gastroenterology. 123:1311–22.CrossRefGoogle Scholar
  36. 36.
    Song AM, et al. (2002) Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury. Am. J. Physiol. Gastrointest. Liver Physiol. 283:G1166–74.CrossRefGoogle Scholar
  37. 37.
    Reid G, et al. (2003) The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal anti-inflammatory drugs. Proc. Natl. Acad. Sci. U. S. A. 100:9244–49.CrossRefGoogle Scholar
  38. 38.
    Sauna ZE, Nandigama K, Ambudkar SV. (2004) Multidrug resistance protein 4 (ABCC4)-mediated ATP hydrolysis: effect of transport substrates and characterization of the post-hydrolysis transition state. J. Biol. Chem. 279:48855–64.CrossRefGoogle Scholar
  39. 39.
    Rius M, Thon WF, Keppler D, Nies AT. (2005). Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. J. Urol. 174:2409–14.CrossRefGoogle Scholar
  40. 40.
    Lin ZP, et al. (2008) Disruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response. Mol. Pharmacol. 73:243–51.CrossRefGoogle Scholar
  41. 41.
    Kochel TJ, et al. (2013) Multiple drug resistance-associated protein 4 (MRP4) may contribute to breast cancer progression by exporting the COX-2 product PGE2. Cancer Res. 73 (Suppl. 1):Abstract 5119.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • María Silvia Ventimiglia
    • 1
  • Ana Clara Najenson
    • 1
  • Juan Carlos Perazzo
    • 1
  • Alejandro Carozzo
    • 3
  • Marcelo S. Vatta
    • 2
  • Carlos A. Davio
    • 3
  • Liliana G. Bianciotti
    • 1
  1. 1.Cátedra de Fisiopatología, Instituto de Inmunología, Genética y Metabolismo (INIGEM-CONICET), Facultad de Farmacia y BioquímicaUniversidad de Buenos Aires. Junín 956Buenos AiresArgentina
  2. 2.Cátedra de Fisiología-Instituto de Química y Metabolismo del Fármaco (IQUIMEFA-CONICET)Buenos AiresArgentina
  3. 3.Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Facultad de Farmacia y BioquímicaUniversidad de Buenos AiresBuenos AiresArgentina

Personalised recommendations