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The exocrine pancreas is an extracardiac source of atrial natriuretic peptide

  • Signaling and cell physiology
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Abstract

Previous studies have shown that atrial natriuretic peptide (ANP) regulates exocrine pancreatic function in health and disease. As extracardiac sources of ANP have been identified and ANP-like immunoreactivity has been reported in the exocrine pancreas, in the present work we sought to establish whether ANP was produced in the rat exocrine pancreas and if conditions like fasting/feeding or acute pancreatitis were reflected on ANP expression. By using RT-PCR, immunoblotting, and immunofluorescence microscopy assays, it was found that both mRNA and protein ANP were present in the acinar cells of the exocrine pancreas. The amount of ANP in the pancreas was lower in than the atrium but similar to other tissues like the kidney and liver. Immunogold labeling electron microscopy studies revealed that ANP was localized in zymogen granules and the endoplasmic reticulum suggesting local synthesis and package into granules. ANP protein expression was significantly increased not only in fasting but also in acute pancreatitis, the latter probably related to impaired secretion. Natriuretic peptide receptor type C which mediates ANP biological effects in the exocrine pancreas was also present in acinar cells and its expression did not change with either fasting or acute pancreatitis. Present findings show that the exocrine pancreas is a relatively important extracardiac source of ANP and further support previous studies strongly suggesting the active role of the peptide in pancreatic physiology and pathophysiology.

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References

  1. Anand-Srivastava MB, Sairam MR, Cantin M (1990) Ring-deleted analogs of atrial natriuretic factor inhibit adenylate cyclase/cAMP system. Possible coupling of clearance atrial natriuretic factor receptors to adenylate cyclase/cAMP signal transduction system. J Biol Chem 265:8566–8572

    CAS  PubMed  Google Scholar 

  2. Arejian M, Li Y, Anand-Srivastava MB (2009) Nitric oxide attenuates the expression of natriuretic peptide receptor C and associated adenylyl cyclase signaling in aortic vascular smooth muscle cells: role of MAPK. Am J Physiol Heart Circ Physiol 296:H1859–H1867. https://doi.org/10.1152/ajpheart.01108.2008

    Article  CAS  PubMed  Google Scholar 

  3. Chabot JG, Morel G, Kopelman H, Belles-Isles M, Heisler S (1987) Atrial natriuretic factor and exocrine pancreas: autoradiographic localization of binding sites and ultrastructural evidence for internalization of endogenous ANF. Pancreas 2:404–413

    Article  CAS  PubMed  Google Scholar 

  4. Chabot JG, Morel G, Belles-Isles M, Jeandel L, Heisler S (1988) ANF and exocrine pancreas: ultrastructural autoradiographic localization in acinar cells. Am J Phys 254:E301–E309. https://doi.org/10.1152/ajpendo.1988.254.3.E301

    Article  CAS  Google Scholar 

  5. Dagnino L, Drouin J, Nemer M (1991) Differential expression of natriuretic peptide genes in cardiac and extracardiac tissues. Mol Endocrinol 5:1292–1300. https://doi.org/10.1210/mend-5-9-1292

    Article  CAS  PubMed  Google Scholar 

  6. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (1981) A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 28:89–94

    Article  PubMed  Google Scholar 

  7. de Bold AJ, Bruneau BG, Kuroski de Bold ML (1996) Mechanical and neuroendocrine regulation of the endocrine heart. Cardiovasc Res 31:7–18

    Article  PubMed  Google Scholar 

  8. Flynn TG, de Bold ML, de Bold AJ (1983) The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties. Biochem Biophys Res Commun 117:859–865

    Article  CAS  PubMed  Google Scholar 

  9. Gerbes AL, Dagnino L, Nguyens T, Nemer M (1994) Transcription of brain natriuretic peptide and atrial natriuretic peptide genes in human tissues. J Clin Endocrinol Metab 78:1307–1311. https://doi.org/10.1210/jcem.78.6.8200930

    Article  CAS  PubMed  Google Scholar 

  10. Gower WR, Dietz JR, Vesely DL, Finley CL, Skolnick KA, Fabri PJ, Chalfant CE (1994) Atrial natriuretic peptide gene expression in the rat gastrointestinal tract. Biochem Biophys Res Commun 202:562–570. https://doi.org/10.1006/bbrc.1994.1965

    Article  CAS  PubMed  Google Scholar 

  11. Gower WR, Salhab KF, Foulis WL, Pillai N, Bundy JR, Vesely DL, Fabri PJ, Dietz JR (2000) Regulation of atrial natriuretic peptide gene expression in gastric antrum by fasting. Am J Phys Regul Integr Comp Phys 278:R770–R780. https://doi.org/10.1152/ajpregu.2000.278.3.R770

    Article  CAS  Google Scholar 

  12. Gower WR, Premaratne S, Mc Cuen RW, Arimura A, McAfee Q, Schubert ML (2003a) Gastric atrial natriuretic peptide regulates endocrine secretion in antrum and fundus of human and rat stomach. Am J Physiol Gastrointest Liver Physiol 284:G638–G645. https://doi.org/10.1152/ajpgi.00427.2002

    Article  CAS  PubMed  Google Scholar 

  13. Gower WR, William R, Dietz JR, Mc Cuen RW, Fabri PJ, Lerner EA, Schubert ML (2003b) Regulation of atrial natriuretic peptide secretion by cholinergic and PACAP neurons of the gastric antrum. Am J Physiol Gastrointest Liver Physiol 284:G68–G74. https://doi.org/10.1152/ajpgi.00113.2002

    Article  CAS  PubMed  Google Scholar 

  14. Gutkowska J, Nemer M, Sole MJ, Drouin J, Sirois P (1989) Lung is an important source of atrial natriuretic factor in experimental cardiomyopathy. J Clin Invest 83:1500–1504. https://doi.org/10.1172/JCI114044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Inagami T, Tanaka I, McKenzie JC, Nakamaru M, Takayanagi R, Imada T, Pochet R, Resibois A, Naruse M, Naruse K et al (1989) Discovery of atrial natriuretic factor in the brain: its characterization and cardiovascular implication. Cell Mol Neurobiol 9:75–85

    Article  CAS  PubMed  Google Scholar 

  16. Jankowski M, Petrone C, Tremblay J, Gutkowska J (1996) Natriuretic peptide system in the rat submaxillary gland. Regul Pept 62:53–61

    Article  CAS  PubMed  Google Scholar 

  17. Lankisch PG, Apte M, Banks PA (2015) Acute pancreatitis. Lancet 386:85–96. https://doi.org/10.1016/S0140-6736(14)60649-8

    Article  Google Scholar 

  18. Lindop GBM, Mallon EA, MacIntyre G (1986) Atrial natriuretic peptide in the heart and pancreas. Histol Histopathol 1:147–154

    CAS  PubMed  Google Scholar 

  19. Lu Z, Kolodecik TR, Karne S, Nyce M, Gorelick F (2003) Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini. Am J Physiol Gastrointest Liver Physiol 285:G822–G828. https://doi.org/10.1152/ajpgi.00213.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mareninova OA, Hermann K, French SW, O’Konski MS, Pandol SJ, Webster P, Erickson AH, Katunuma N, Gorelick FS, Gukovsky I, Gukovsky I, Gukovskaya AS (2009) Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest 119:3340–3355. https://doi.org/10.1172/JCI38674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Martinez Seeber A, Vidal NA, Carchio SM, Karara AL (1986) Inhibition of water-sodium intestinal absorption by an atrial extract. Can J Physiol Pharmacol 64:244–247

    Article  CAS  PubMed  Google Scholar 

  22. Mukherjee R, Mareninova OA, Odinokova IV, Huang W, Murphy J, Chvanov M, Javed MA, Wen L, Booth DM, Cane MC, Awais M, Gavillet B, Pruss RM, Schaller S, Molketin JD, Tpikin AV, Petersen OH, Pandol SJ, Gukivsky I, Criddle DN, Gukovskaya AS, Sutton R, Pancreas Biomedical Research Unit NIHR (2016) Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut 65:1333–1346. https://doi.org/10.1136/gutjnl-2014-308553

    Article  CAS  PubMed  Google Scholar 

  23. Najenson AC, Courreges AP, Perazzo JC, Rubio MF, Vatta MS, Bianciotti LG (2018) Atrial natriuretic peptide reduces inflammation and enhances apoptosis in rat acute pancreatitis. Acta Physiol (Oxf) 222:e12992. https://doi.org/10.1111/apha.12992

    Article  CAS  Google Scholar 

  24. Ogawa T, Bruneau BG, Yokota N, de Bold ML, de Bold AJ (1997) Tissue-specific regulation of renal and cardiac atrial natriuretic factor gene expression in deoxycorticosterone acetate-salt rats. Hypertension 30:1342–1347

    Article  CAS  PubMed  Google Scholar 

  25. Perides G, Sharma A, Gopal A, Tao X, Dwyer K, Ligon B, Steer ML (2005) Secretin differentially sensitizes rat pancreatic acini to the effects of supramaximal stimulation with caerulein. Am J Physiol Gastrointest Liver Physiol 289:G713–G721. https://doi.org/10.1152/ajpgi.00519.2004

    Article  CAS  PubMed  Google Scholar 

  26. Rodríguez MR, Diez F, Ventimiglia MS, Morales V, Copsel S, Vatta MS, Davio CA, Bianciotti LG (2011) Atrial natriuretic factor stimulates efflux of cAMP in rat exocrine pancreas via multidrug resistance-associated proteins. Gastroenterology 140:1292–1302. https://doi.org/10.1053/j.gastro.2010.12.053

    Article  CAS  PubMed  Google Scholar 

  27. Sabbatini ME (2009) Natriuretic peptides as regulatory mediators of secretory activity in the digestive system. Regul Pept 154:5–15. https://doi.org/10.1016/j.regpep.2009.02.009

    Article  CAS  PubMed  Google Scholar 

  28. Sabbatini ME, Villagra A, Davio CA, Vatta MS, Fernández BE, Bianciotti LG (2003) Atrial natriuretic factor stimulates exocrine pancreatic secretion in the rat through NPR-C receptors. Am J Physiol Gastrointest Liver Physiol 285:G929–G937. https://doi.org/10.1152/ajpgi.00010.2003

    Article  CAS  PubMed  Google Scholar 

  29. Sabbatini ME, Rodriguez M, di Carlo MB, Davio CA, Vatta MS, Bianciotti LG (2007a) C-type natriuretic peptide enhances amylase release through NPR-C receptors in the exocrine pancreas. Am J Physiol Gastrointest Liver Physiol 293:G987–G994. https://doi.org/10.1152/ajpgi.00268.2007

    Article  CAS  PubMed  Google Scholar 

  30. Sabbatini ME, Vatta MS, Davio CA, Bianciotti LG (2007b) Atrial natriuretic factor negatively modulates secretin intracellular signaling in the exocrine pancreas. Am J Physiol Gastrointest Liver Physiol 292:G349–G357. https://doi.org/10.1152/ajpgi.00163.2006

    Article  CAS  PubMed  Google Scholar 

  31. Schlueter N, de Sterke A, Willmes DN, Spranger J, Jondan J, Birkenfeld AL (2014) Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome. Pharmacol Ther 144:12–27. https://doi.org/10.1016/j.pharmthera.2014.04.007

    Article  CAS  PubMed  Google Scholar 

  32. Somlyo AV, Broderick R, Shuman H, Buhle EL, Somlyo AP (1988) Atrial-specific granules in situ have high calcium content, are acidic, and maintain anion gradients. Proc Natl Acad Sci 85:6222–6226

    Article  CAS  PubMed  Google Scholar 

  33. Ventimiglia MS, Najenson AC, Perazzo JC, Carozzo A, Vatta MS, Davio CA, Bianciotti LG (2015) Blockade of multidrug resistance-associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor’s beneficial effect in rats: role of MRP4 (ABCC4). Mol Med 21:58–67. https://doi.org/10.2119/molmed.2014.00166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vesely DL, Palmer PA, Giordano AT (1992) Atrial natriuretic factor prohormone peptides are present in a variety of tissues. Peptides 13:165–170

    Article  CAS  PubMed  Google Scholar 

  35. Williams JA, Korc M, Dormer RL (1978) Action of secretagogues on a new preparation of functionally intact, isolated pancreatic acini. Am J Physiol 235:517–524

    CAS  PubMed  Google Scholar 

  36. Woodard GE, Li X, Rosado JA (2005) Characteristics of the renal C-type natriuretic peptide receptor in hypertrophied and developing rat kidney. J Mol Endocrinol 35:519–530. https://doi.org/10.1677/jme.1.01871.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Mrs. Margarita Lopez from the Instituto de Biologia Celular y Neurociencia (IBCN-CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires for excellent technical assistance with immunogold labeling studies.

Funding

This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) (PICT2012-2755 and PICT2015-2030) and Universidad de Buenos Aires (UBACYT 20020130100811BA).

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Correspondence to Liliana G. Bianciotti.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Najenson, A.C., Bianchi, M., Courreges, A.P. et al. The exocrine pancreas is an extracardiac source of atrial natriuretic peptide. Pflugers Arch - Eur J Physiol 471, 915–924 (2019). https://doi.org/10.1007/s00424-018-02247-y

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