Irbesartan Prevents Metabolic Syndrome in Rats via Activation of Peroxisome Proliferator-Activated Receptor γ

Takai, Shinji; Jin, Denan; Miyazaki, Mizuo

doi:10.1254/jphs.11053fp

Cited by 14 publications

(9 citation statements)

References 46 publications

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“…Moreover, the numbers of EGFP + F4/80 + CCR2 + monocytic cells and EGFP + PaSCs in the pancreas decreased after treatment with irbesartan. Because irbesartan is known to act as not only an antagonist of AT1R and CCR2 but also a partial agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ) [28], [53], the migration of monocytes into the injured pancreas may be prevented owing to its dual properties as a CCR2 antagonist and a PPAR-γ agonist. Furthermore, as Ang II-induced MCP-1 production in the pancreas is reduced by AT1R antagonists [54], irbesartan may also inhibit monocyte infiltration through the decrease of MCP-1.…”

Section: Discussionmentioning

confidence: 99%

Monocytes Infiltrate the Pancreas via the MCP-1/CCR2 Pathway and Differentiate into Stellate Cells

et al. 2014

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Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)+CD45– cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP+CD45– cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and α-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP+ PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6Chigh monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP+F4/80+CCR2+ monocytic cells and EGFP+ PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP+ bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP+ PaSCs in injured mice. We propose that CCR2+ monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs.

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Section: Discussionmentioning

confidence: 99%

Monocytes Infiltrate the Pancreas via the MCP-1/CCR2 Pathway and Differentiate into Stellate Cells

et al. 2014

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“…Augmentation of angiotensin II stimulation may be related to not only the development of diabetes but also to the pathogenesis of diabetic complications (21). Blockade of angiotensin II is associated with increases in insulin-stimulated skeletal muscle glucose transport and the glucose transporter GLUT-4 in skeletal muscle.…”

Section: Effects Of Chymase Inhibitors In Diabetesmentioning

confidence: 99%

Multiple Mechanisms for the Action of Chymase Inhibitors

Jin

Miyazaki

2012

J Pharmacol Sci

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Abstract. Angiotensin II plays an important role in regulating blood pressure. Moreover, angiotensin II directly promotes organ damage by inducing expression of various genes, such as transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors. Blockade of angiotensin II has been shown to not only lower blood pressure, but also to prevent cardiovascular and renal dysfunction and fibrosis. Inhibition of TGF-β and MMP-9 has also been shown to prevent cardiovascular and renal damage. A mast cell-produced enzyme, chymase, generates angiotensin II and also converts precursors of TGF-β and MMP-9 to their active forms. Chymase also strongly promotes accumulation of inflammatory cells. These multiple functions of chymase may play an important role in the development and promotion of various diseases. In fact, chymase inhibitors have been shown to prevent nonalcoholic steatohepatitis, intestinal inflammation, and adhesion formation after surgery and cardiovascular and renal damage. On the other hand, chymase inhibitors, unlike angiotensin-converting enzyme inhibitors and angiotensin II blockers, have no blood pressure-lowering effect despite blocking angiotensin II formation. Thus, chymase inhibitors may be useful for preventing damage to various organs via multiple mechanisms without lowering blood pressure.

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“…The total RNA (1 μg) of the aorta was transcribed into cDNA with Superscript III reverse transcriptase and random hexamers (Invitrogen, Carlsbad, CA, USA). 14 The mRNA was measured by RT-PCR on a LightCycler with software (Roche Diagnostics, Tokyo, Japan) using TaqMan fluorogenic probes. All primers and probes for RT-PCR of ACE and ACE2, endothelial nitric oxidase synthase (eNOS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1), voltage-dependent N-type calcium channel (Ca V 2.2) and GAPDH were designed by Roche Diagnostics.…”

Section: Methodsmentioning

confidence: 99%

“…For immunostaining against 4-hydroxy-2-nonenal (4-HNE), sections were incubated with mouse 4-HNE antibody (Nikken Seil, Shizuoka, Japan). 14 A secondary biotinylated anti-IgG antibody (Invitrogen) was used. Sections were visualized using horseradish peroxidase and 3-amino-9-ethylcarbozole as the substrate-chromogen (Dako).…”

Section: Methodsmentioning

confidence: 99%

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Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats

et al. 2012

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Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg−1), valsartan (10 mg kg−1) and amlodipine (1 mg kg−1), and valsartan (10 mg kg−1) and cilnidipine (1 mg kg−1) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.

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Irbesartan Prevents Metabolic Syndrome in Rats via Activation of Peroxisome Proliferator-Activated Receptor γ

Cited by 14 publications

References 46 publications

Monocytes Infiltrate the Pancreas via the MCP-1/CCR2 Pathway and Differentiate into Stellate Cells

Monocytes Infiltrate the Pancreas via the MCP-1/CCR2 Pathway and Differentiate into Stellate Cells

Multiple Mechanisms for the Action of Chymase Inhibitors

Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats

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