Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models

Miyazaki, Mizuo; Takai, Shinji; Jin, Denan; Muramatsu, Michiko

doi:10.1016/j.pharmthera.2006.05.008

Cited by 103 publications

(98 citation statements)

References 81 publications

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“…Mast cells store abundant chymase in secretory granules. On release, chymase binds to the extracellular matrix and continues to function for several weeks (34). It is generally distributed in cardiovascular tissues along with the infiltration of chymase-positive inflammatory cells into the interstitium.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters

Maeda

Inoguchi

Takei³

et al. 2010

American Journal of Physiology-Renal Physiology

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Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters. Am J Physiol Renal Physiol 299: F1328 -F1338, 2010. First published September 29, 2010 doi:10.1152/ajprenal.00337.2010.-Accumulating evidence suggests that the intrarenal renin-angiotensin system may be involved in the progression of diabetic nephropathy. Chymase is a potent local angiotensin II-forming enzyme in several species, including humans and hamsters. However, the pathophysiological role of chymase is not fully understood. Here, we report a causal role of chymase in diabetic nephropathy and the therapeutic effectiveness of chymase inhibition. In the present study, renal chymase expression was markedly upregulated in streptozotocin-induced diabetic hamsters. Oral administration of a specific chymase inhibitor, TEI-F00806, completely ameliorated proteinuria, the overexpression of transforming growth factor-␤ and fibronectin in glomeruli, and renal mesangial expansion, by normalizing the increase in intrarenal angiotensin II levels in diabetic hamsters independently of blood pressure levels. In contrast, ramipril did not show such sufficient effects. These effects occurred in parallel with improvements in superoxide production and expression of NAD(P)H oxidase components [NAD(P)H oxidase 4 and p22 phox ] in glomeruli. This study showed for the first time that chymase inhibition may protect against elevated intrarenal angiotensin II levels, oxidative stress, and renal dysfunction in diabetes. These findings suggest that chymase offers a new therapeutic target for diabetic nephropathy.angiotensin II; NAD(P)H oxidase DIABETIC NEPHROPATHY IS A leading cause of renal failure worldwide and is associated with an increased risk of cardiovascular events. Experimental and clinical trials have indicated that blockade of the renin-angiotensin system (RAS) with angiotensin I-converting enzyme (ACE) inhibitors or angiotensin II (ANG II) antagonists has some protective effects on diabetic nephropathy and on cardiovascular events (3, 4, 32), which appear to be independent of its antihypertensive effect. These findings suggest that the intrarenal RAS may be involved in the progression of diabetic nephropathy. It is well recognized that the ACE-dependent ANG II-generating system is a source of intrarenal ANG II production. However, the use of ACE inhibitors was reported to only partly reduce the intrarenal ANG II production (10), suggesting the existence of alternative pathways. Indeed, human chymase specifically hydrolyzes the Phe 8 -His 9 bond in ANG I and forms ANG II (26). Tissue chymase of other several species including the hamster also have more efficient ANG II-forming activities than ACE, while rat chymase degrades ANG II inversely (1, 26). Of note, several reports have shown that chymase expression may be upregulated in diabetic renal tissues (14,19,29). However, it is still unclear whether chymase substantially contributes to the activation of intrarenal RAS in diabetic renal tissues. More importantly, th...

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Section: Discussionmentioning

confidence: 99%

Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters

Maeda

Inoguchi

Takei³

et al. 2010

American Journal of Physiology-Renal Physiology

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“…Although captopril inhibits ACE1, it does not affect the activity of other proteases, such as chymase, which have been shown to increase in cardiac tissues with MI (6,22). Thus, although the normal pathways for ANG II production are inhibited by captopril, the alternative pathways for generating ANG II are unaffected by drug treatment, and may be of greater importance in elevating local ANG II levels within the cardiac interstitium (6,22). This suggests that inhibition of ACE1 activity by captopril is insufficient to alter the effects of disease-induced increases in ANG II levels within the guinea pig cardiac plexus.…”

Section: Discussionmentioning

confidence: 99%

“…The increased sensitivity to NE was still observed in the neurons, and there was no ANG II-induced potentiation of adrenergic or muscarinic responses in the MI animals treated with captopril for 6 wk. Although captopril inhibits ACE1, it does not affect the activity of other proteases, such as chymase, which have been shown to increase in cardiac tissues with MI (6,22). Thus, although the normal pathways for ANG II production are inhibited by captopril, the alternative pathways for generating ANG II are unaffected by drug treatment, and may be of greater importance in elevating local ANG II levels within the cardiac interstitium (6,22).…”

Section: Discussionmentioning

confidence: 99%

“…Increased sympathetic activity evokes elevated levels of norepinephrine (NE) release within the heart (7). An increase in the synthesis of ANG II from both enhanced renin release and increased protease activity within the heart interstitial tissues contributes to the hyperdynamic sympathetic response (6,21,24). Inhibition of adrenergic receptors (e.g., ␤-blockade) or treatment with drugs that target ANG II synthesis (ACE inhibitors) or receptor activation (AT 1 inhibitors) has been demonstrated to alter adverse remodeling of the cardiac muscle (30).…”

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confidence: 99%

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Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

Hardwick

Ryan

Powers

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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), or AT2 receptor agonist (CGP42112A, 0.14 mg·kg Ϫ1 ·day Ϫ1 ) on remodeling of the guinea pig intrinsic cardiac plexus following chronic myocardial infarction (MI). MI was surgically induced and animals recovered for 6 or 7 wk, with or without drug treatment. Intracellular voltage recordings from whole mounts of the cardiac plexus were used to monitor changes in neuronal responses to norepinephrine (NE), muscarinic agonists (bethanechol), or ANG II. MI produced an increase in neuronal excitability with NE and a loss of sensitivity to ANG II. MI animals treated with captopril exhibited increased neuronal excitability with NE application, while MI animals treated with CGP42112A did not. Losartan treatment of MI animals did not alter excitability with NE compared with untreated MIs, but these animals did show an enhanced synaptic efficacy. This effect on synaptic function was likely due to presynaptic AT1 receptors, since ANG II was able to reduce output to nerve fiber stimulation in control animals, and this effect was prevented by inclusion of losartan in the bath solution. Analysis of AT receptor expression by Western blot showed a decrease in both AT 1 and AT2 receptors with MI that was reversed by all three drug treatments. These data indicate that neuronal remodeling of the guinea pig cardiac plexus following MI is mediated, in part, by activation of both AT 1 and AT2 receptors.

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“…2,83,84 Adipose tissue, macrophages and mast cells in the adventitia of atherosclerotic and/or aneurysmal aorta, 85 and fibroblasts in the interstitium of the heart 86, 87 have been shown to contribute to Ang II generation. Immunoreactivity of angiotensin-converting enzyme (ACE) was increased and distributed in the perivascular and interstitial fibroblasts of the pressure-overloaded rat left ventricle (Figure 3).…”

Section: Bioactive Moleculesmentioning

confidence: 99%

Stromal Cell Biology - A Way to Understand the Evolution of Cardiovascular Diseases -

Tsuruda

Imamura

Hatakeyama

et al. 2010

Circ J

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Stromal cells, composed of fibroblasts, microvascular endothelial cells, immune cells and inflammatory cells, are critical determinants of the mechanical properties and function of the heart and vasculature, and the mechanisms whereby these types of cells are activated are important to understand the progression of cardiovascular diseases. Emerging studies have suggested that the activation of autocrine and paracrine signaling pathways by stromal cell-derived growth factors, cytokines and bioactive molecules contributes to disease progression. Disruption of the stromal network will result in alterations in the geometry and function in these organs. Interventions targeting the stromal cells (eg, myofibroblasts, microvascular endothelial cells, inflammatory cells) by pharmacological agents or direct gene delivery/small interfering RNA would be potential novel therapeutic strategies to prevent/attenuate the progression of cardiovascular disorders. (Circ J 2010; 74: 1042 - 1050

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Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models

Cited by 103 publications

References 81 publications

Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters

Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters

Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

Stromal Cell Biology - A Way to Understand the Evolution of Cardiovascular Diseases -

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