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

Autores
Ventimiglia, Maria Silvia; Najenson, Ana Clara; Perazzo, Juan Carlos; Carozzo, Alejandro Enrique; Vatta, Marcelo Sergio; Davio, Carlos Alberto; Bianciotti, Liliana Graciela
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Ventimiglia, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Najenson, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Perazzo, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Carozzo, Alejandro Enrique. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vatta, Marcelo Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco (i); Argentina
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bianciotti, Liliana Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Materia
MRPs
acute pancreatitis
secretin
cAMP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/13823
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/13823
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4Ventimiglia, Maria SilviaNajenson, Ana ClaraPerazzo, Juan CarlosCarozzo, Alejandro EnriqueVatta, Marcelo SergioDavio, Carlos AlbertoBianciotti, Liliana GracielaMRPsacute pancreatitissecretincAMPhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3We 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.Fil: Ventimiglia, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Najenson, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Perazzo, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Carozzo, Alejandro Enrique. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vatta, Marcelo Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco (i); ArgentinaFil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bianciotti, Liliana Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFeinstein Inst Med Res2015-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/13823Ventimiglia, Maria Silvia; Najenson, Ana Clara; Perazzo, Juan Carlos; Carozzo, Alejandro Enrique; Vatta, Marcelo Sergio; et al.; Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4; Feinstein Inst Med Res; Molecular Medicine; 21; 1; 5-2015; 58-671076-15511528-3658enginfo:eu-repo/semantics/altIdentifier/url/http://molmed.org/journal/articles/43/1753info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461582/info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.2119/molmed.2014.00166info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:53:58Zoai:ri.conicet.gov.ar:11336/13823instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:53:58.956CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
title Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
spellingShingle 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
MRPs
acute pancreatitis
secretin
cAMP
title_short Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
title_full Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
title_fullStr Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
title_full_unstemmed Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
title_sort Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4
dc.creator.none.fl_str_mv Ventimiglia, Maria Silvia
Najenson, Ana Clara
Perazzo, Juan Carlos
Carozzo, Alejandro Enrique
Vatta, Marcelo Sergio
Davio, Carlos Alberto
Bianciotti, Liliana Graciela
author Ventimiglia, Maria Silvia
author_facet Ventimiglia, Maria Silvia
Najenson, Ana Clara
Perazzo, Juan Carlos
Carozzo, Alejandro Enrique
Vatta, Marcelo Sergio
Davio, Carlos Alberto
Bianciotti, Liliana Graciela
author_role author
author2 Najenson, Ana Clara
Perazzo, Juan Carlos
Carozzo, Alejandro Enrique
Vatta, Marcelo Sergio
Davio, Carlos Alberto
Bianciotti, Liliana Graciela
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv MRPs
acute pancreatitis
secretin
cAMP
topic MRPs
acute pancreatitis
secretin
cAMP
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Ventimiglia, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Najenson, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Perazzo, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Carozzo, Alejandro Enrique. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vatta, Marcelo Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco (i); Argentina
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bianciotti, Liliana Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
description 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.
publishDate 2015
dc.date.none.fl_str_mv 2015-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/13823
Ventimiglia, Maria Silvia; Najenson, Ana Clara; Perazzo, Juan Carlos; Carozzo, Alejandro Enrique; Vatta, Marcelo Sergio; et al.; Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4; Feinstein Inst Med Res; Molecular Medicine; 21; 1; 5-2015; 58-67
1076-1551
1528-3658
url http://hdl.handle.net/11336/13823
identifier_str_mv Ventimiglia, Maria Silvia; Najenson, Ana Clara; Perazzo, Juan Carlos; Carozzo, Alejandro Enrique; Vatta, Marcelo Sergio; et al.; Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4; Feinstein Inst Med Res; Molecular Medicine; 21; 1; 5-2015; 58-67
1076-1551
1528-3658
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://molmed.org/journal/articles/43/1753
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461582/
info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.2119/molmed.2014.00166
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Feinstein Inst Med Res
publisher.none.fl_str_mv Feinstein Inst Med Res
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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