Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II–Generating Pathway in Diabetic Complications

Koka, Vijay; Wang, Wansheng; Huang, Xiao Ru; Kim‐Mitsuyama, Shokei; Truong, Luan D.; Lan, Hui‐Yao

doi:10.1161/circulationaha.105.575589

Cited by 72 publications

(54 citation statements)

References 40 publications

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“…In the present study, the lack of reduction in iAng II levels after only 1 week of ACE-inhibitor treatment strongly suggests an ACE-independent mechanism of iAng II synthesis, corroborating in vitro observations. Upregulation of vascular chymase in diabetic patients and chymasemediated Ang II generation in human and rat VSMCs and human mesangial cells has been previously reported (15,17,18,35). Involvement of chymase further strengthens the concept of an intracellular RAS in diabetes.…”

Section: Discussionsupporting

confidence: 58%

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Singh

Khode³

et al. 2008

Diabetes

293

239

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OBJECTIVE— Many of the effects of angiotensin (Ang) II are mediated through specific plasma membrane receptors. However, Ang II also elicits biological effects from the interior of the cell (intracrine), some of which are not inhibited by Ang receptor blockers (ARBs). Recent in vitro studies have identified high glucose as a potent stimulus for the intracellular synthesis of Ang II, the production of which is mainly chymase dependent. In the present study, we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system (RAS) in vivo and whether ARBs, ACE, or renin inhibitors block synthesis and effects of intracellular Ang II (iAng II). RESEARCH DESIGN AND METHODS— Diabetes was induced in adult male rats by streptozotocin. Diabetic rats were treated with insulin, candesartan (ARB), benazepril (ACE inhibitor), or aliskiren (renin inhibitor). RESULTS— One week of diabetes significantly increased iAng II levels in cardiac myocytes, which were not normalized by candesartan, suggesting that Ang II was synthesized intracellularly, not internalized through AT 1 receptor. Increased intracellular levels of Ang II, angiotensinogen, and renin were observed by confocal microscopy. iAng II synthesis was blocked by aliskiren but not by benazepril. Diabetes-induced superoxide production and cardiac fibrosis were partially inhibited by candesartan and benazepril, whereas aliskiren produced complete inhibition. Myocyte apoptosis was partially inhibited by all three agents. CONCLUSIONS— Diabetes activates the cardiac intracellular RAS, which increases oxidative stress and cardiac fibrosis. Renin inhibition has a more pronounced effect than ARBs and ACE inhibitors on these diabetes complications and may be clinically more efficacious.

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Section: Discussionsupporting

confidence: 58%

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Singh

Khode³

et al. 2008

Diabetes

293

239

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“…The characterization and transfection of these dominant negative vectors, as well as a negative control, has been well described elsewhere. 14,15 Briefly, HK-2 cells were incubated with the adenovirus at multiplicity of infection of 30 in DMEM for 1 hour, and then made quiescent for 24 hours before stimulation with Ang II. Each experiment was repeated at least thrice throughout the study.…”

Section: Cell Culturementioning

confidence: 99%

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Koka

Huang

Chung

et al. 2008

The American Journal of Pathology

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262

258

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The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to upregulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage. The prevalence of hypertension is approximately 30% based on National Health and Nutrition Examination Survey data, 1 making it one of the most important risk factors for cardiovascular disease, the major cause of mortality in the United States.The recent discovery of the angiotensin II (Ang II) breakdown enzyme angiotensin I -converting enzyme (ACE)2 and alternative Ang II-generating pathways such as chymase, in addition to ACE, has increased the complexity of our understanding of Ang II generation and degradation in hypertension. 2,3 ACE2 is a breakdown enzyme responsible for the degradation of Ang II to Angiotensin 1-7 peptide. The later has vasodilatory properties and has its own unique receptor, the Mas receptor. 3 Emerging evidence shows that ACE2 plays an important role in negatively regulating hypertension. In rat models of hypertension, renal ACE2 mRNA and protein are decreased, although this could not be confirmed in human hypertensive nephropathy in a prior study. 4 Further, in rats treated with ACE inhibitors and angiotensin receptor blockers, an increase in local renal ACE2 activity is noted. 5,6 We have shown earlier that ACE is up-regulated in human diabetic nephropathy accompanied with hypertension, a condition associated with high Ang II levels. 7 Taken together, these findings suggest that there may be an alteration in the ACE/ACE2 balance in hypertension in a manner that favors increased Ang II generation (ie, upre...

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“…The AGEs and the S100/Calgranulins are those which have been most studied as agents of proinflammatory signalling [43,105] and which appear to trigger intercellular signalling mechanisms that could participate in some of the pathologies associated with diabetes, such as nephropathy [91], retinopathy [14], cardiovascular diseases [68] and loss of bone mass [42].…”

Section: Ages and Chronic Diabetic Complicationsmentioning

confidence: 99%

Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity

Magalhães

Appell

Duarte

2008

Eur Rev Aging Phys Act

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Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II–Generating Pathway in Diabetic Complications

Cited by 72 publications

References 40 publications

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity

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