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Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.

Lacraz G, Giroix MH, Kassis N, Coulaud J, Galinier A, Noll C, Cornut M, Schmidlin F, Paul JL, Janel N, Irminger JC, Kergoat M, Portha B, Donath MY, Ehses JA, Homo-Delarche F - PLoS ONE (2009)

Bottom Line: All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets.IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France.

ABSTRACT

Background: Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra).

Methodology/principal findings: Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.

Conclusions/significance: GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.

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IL-1Ra treatment reduces the expression of most of the selected genes for endothelial activation, oxidative stress, myeloid cells, and fibrosis in GK islets.Pancreatic islets were isolated from GK rats following 1-month-treatment with IL-1Ra by s.c. injections (GK saline n = 6, GK IL-1Ra (100 mg/kg/day), n = 5). For each animal, total RNA was extracted from isolated islets and quantitative RT-PCR was performed for the indicated genes, and expressed relative to GK saline. *p<0.05 using Student's t-test.
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pone-0006963-g001: IL-1Ra treatment reduces the expression of most of the selected genes for endothelial activation, oxidative stress, myeloid cells, and fibrosis in GK islets.Pancreatic islets were isolated from GK rats following 1-month-treatment with IL-1Ra by s.c. injections (GK saline n = 6, GK IL-1Ra (100 mg/kg/day), n = 5). For each animal, total RNA was extracted from isolated islets and quantitative RT-PCR was performed for the indicated genes, and expressed relative to GK saline. *p<0.05 using Student's t-test.

Mentions: GK rat IL-1Ra treatment down-regulated 80% of selected genes. As shown in Fig. 1A, IL-1Ra treatment significantly (except otherwise stated) decreased GK islet expression of genes encoding: PAI-1 (−61%), VCAM-1 (−68%, ns), ACE-1 (−74%), ET-1 (Edn1, −54%), NOX-2 (−67%), COX-2 (−60%), iNOS (−54%), prostacyclin synthase (Ptgis, −48%), and eNOS (−55%) vs Wistar controls. However, IL-1Ra treatment did not significantly reduce islet endothelial gene expression for E-selectin (Sele) and HIF-1α.


Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.

Lacraz G, Giroix MH, Kassis N, Coulaud J, Galinier A, Noll C, Cornut M, Schmidlin F, Paul JL, Janel N, Irminger JC, Kergoat M, Portha B, Donath MY, Ehses JA, Homo-Delarche F - PLoS ONE (2009)

IL-1Ra treatment reduces the expression of most of the selected genes for endothelial activation, oxidative stress, myeloid cells, and fibrosis in GK islets.Pancreatic islets were isolated from GK rats following 1-month-treatment with IL-1Ra by s.c. injections (GK saline n = 6, GK IL-1Ra (100 mg/kg/day), n = 5). For each animal, total RNA was extracted from isolated islets and quantitative RT-PCR was performed for the indicated genes, and expressed relative to GK saline. *p<0.05 using Student's t-test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2737103&req=5

pone-0006963-g001: IL-1Ra treatment reduces the expression of most of the selected genes for endothelial activation, oxidative stress, myeloid cells, and fibrosis in GK islets.Pancreatic islets were isolated from GK rats following 1-month-treatment with IL-1Ra by s.c. injections (GK saline n = 6, GK IL-1Ra (100 mg/kg/day), n = 5). For each animal, total RNA was extracted from isolated islets and quantitative RT-PCR was performed for the indicated genes, and expressed relative to GK saline. *p<0.05 using Student's t-test.
Mentions: GK rat IL-1Ra treatment down-regulated 80% of selected genes. As shown in Fig. 1A, IL-1Ra treatment significantly (except otherwise stated) decreased GK islet expression of genes encoding: PAI-1 (−61%), VCAM-1 (−68%, ns), ACE-1 (−74%), ET-1 (Edn1, −54%), NOX-2 (−67%), COX-2 (−60%), iNOS (−54%), prostacyclin synthase (Ptgis, −48%), and eNOS (−55%) vs Wistar controls. However, IL-1Ra treatment did not significantly reduce islet endothelial gene expression for E-selectin (Sele) and HIF-1α.

Bottom Line: All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets.IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France.

ABSTRACT

Background: Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra).

Methodology/principal findings: Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.

Conclusions/significance: GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.

Show MeSH
Related in: MedlinePlus