In Vivo Conditional Pax4 Overexpression in Mature Islet β-Cells Prevents Stress-Induced Hyperglycemia in Mice

Autor: Asllan Gjinovci, Carmen M. Jimenez Moreno, Claes B. Wollheim, Kai Hui Hu He, Deborah Aeberhard, Fabrizio Thorel, Marion Cornu, Benoit R. Gauthier, Petra I. Lorenzo, Jorge Vallejo Ortega, Pedro Luis Herrera, Thierry Brun, Bernard Thorens, Paolo Meda
Přispěvatelé: European Commission, Swiss National Science Foundation, Juvenile Diabetes Research Foundation International, National Institutes of Health (US), Novo Nordisk Foundation, Junta de Andalucía, Fundación Progreso y Salud
Rok vydání: 2011
Předmět:
Apoptosis/genetics/physiology
Maf Transcription Factors
Large
endocrine system diseases
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Streptozocin/toxicity
Apoptosis
Polymerase Chain Reaction
Mice
0302 clinical medicine
Stress
Physiological/physiology
Insulin-Secreting Cells
Proto-Oncogene Proteins c-myc/genetics/metabolism
Insulin
Paired Box Transcription Factors
Glucose Transporter Type 2/genetics/metabolism
Glucose homeostasis
ddc:576.5
Cyclin-Dependent Kinase 4/genetics/metabolism
Homeodomain Proteins/genetics/metabolism
Hyperglycemia/chemically induced/metabolism/prevention & control
Glucose Transporter Type 2
0303 health sciences
geography.geographical_feature_category
biology
Cytochromes c
Islet
Immunohistochemistry
3. Good health
Proto-Oncogene Proteins c-bcl-2
Insulin-Secreting Cells/cytology/metabolism
Cytochromes c/genetics/metabolism
medicine.drug
Genetically modified mouse
endocrine system
medicine.medical_specialty
Maf Transcription Factors
Large/genetics/metabolism
Immunoblotting
Mice
Transgenic
030209 endocrinology & metabolism
Streptozocin
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Stress
Physiological
Internal medicine
Internal Medicine
medicine
Animals
ddc:612
Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
030304 developmental biology
Homeodomain Proteins
Insulin/genetics/metabolism
geography
Apoptosis/genetics
Apoptosis/physiology
Cyclin-Dependent Kinase 4/genetics
Cyclin-Dependent Kinase 4/metabolism
Cytochromes c/genetics
Cytochromes c/metabolism
Glucose Transporter Type 2/genetics
Glucose Transporter Type 2/metabolism
Homeodomain Proteins/genetics
Homeodomain Proteins/metabolism
Hyperglycemia/chemically induced
Hyperglycemia/metabolism
Insulin/genetics
Insulin/metabolism
Insulin-Secreting Cells/cytology
Insulin-Secreting Cells/metabolism
Maf Transcription Factors
Large/genetics
Maf Transcription Factors
Large/metabolism
Paired Box Transcription Factors/genetics
Paired Box Transcription Factors/metabolism
Proto-Oncogene Proteins c-bcl-2/genetics
Proto-Oncogene Proteins c-bcl-2/metabolism
Proto-Oncogene Proteins c-myc/genetics
Proto-Oncogene Proteins c-myc/metabolism
Cyclin-Dependent Kinase 4
Streptozotocin
Paired Box Transcription Factors/genetics/metabolism
Endocrinology
Islet Studies
Hyperglycemia
biology.protein
PAX4
GLUT2
Zdroj: Diabetes
Diabetes, Vol. 60, No 6 (2011) pp. 1705-15
Diabetes; Vol 60
Diabetes, vol. 60, no. 6, pp. 1705-1715
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1939-327X
0012-1797
DOI: 10.2337/db10-1102
Popis: et al.
[Objective]: To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129W) in β-cells. [Research and Methods]: Glucose homeostasis and β-cell death and proliferation were assessed in Pax4- or Pax4R129W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and β-cell markers were studied by immunohistochemistry and quantitative RT-PCR. [Results]: Pax4 but not Pax4R129W protected animals against streptozotocin-induced hyperglycemia and isolated islets from cytokine-mediated β-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1β transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. [Conclusions]: Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-κB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of β-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression.
This work was funded by the Swiss National Science Foundation (grants 310030-119763 to B.R.G.; 310000-116750/1 to C.B.W. and B.R.G.; 310000-109402, 310000-122423, and CR32I3-129987 to P.M.; and 3100A0103867 NCCR “Frontiers-in-Genetics” to P.L.H.), the Juvenile Diabetes Research Foundation (grants 7-2005-1158 to C.B.W. and B.R.G.; 40-2011-11 to P.M.; and 26-2007-928 and 26-2008-640 to P.L.H.), the EU (FP-7, BETAIMAGE 222980, IMI IMIDIA, and C2008-T7 to P.M. and FP-6, β Cell Therapy Consortium to P.L.H.), the National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases (the Beta Cell Biology Consortium to P.L.H.), and the Foundation Progreso y Salud, Junta de Andalucia (to B.R.G.). K.H.H.H. was supported by a GeMet/Novo Nordisk fellowship. No other potential conflicts of interest relevant to this article were reported.
Databáze: OpenAIRE
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