The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis
Open accessAbstract
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 AT1 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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Cites
Physiology of Local Renin-Angiotensin Systems
Paul, M., Poyan Mehr, A., & Kreutz, R. (2006) · Physiological Reviews · doi:10.1152/physrev.00036.2005 · Cited by 1,739
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Myocardial Cell Death in Human Diabetes
Frustaci, A., Kajstura, J., Chimenti, C., Jakoniuk, I., Leri, A., Maseri, A., Nadal-Ginard, B., & Anversa, P. (2000) · Circulation Research · doi:10.1161/01.res.87.12.1123 · Cited by 796
Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity
Schupp, M., Janke, J., Clasen, R., Unger, T., & Kintscher, U. (2004) · Circulation · doi:10.1161/01.cir.0000127955.36250.65 · Cited by 705
Structure-based design of aliskiren, a novel orally effective renin inhibitor
Wood, J. M., Maibaum, J., Rahuel, J., Grütter, M. G., Cohen, N.-C., Rasetti, V., Rüger, H., Göschke, R., Stutz, S., Fuhrer, W., et al. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01451-7 · Cited by 506
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Kajstura, J., Fiordaliso, F., Andreoli, A. M., Li, B., Chimenti, S., Medow, M. S., Limana, F., Nadal-Ginard, B., Leri, A., & Anversa, P. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1414 · Cited by 386
Increased Plasma Inactive Renin in Diabetes Mellitus: A Marker of Microvascular Complications
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Cited by
Diretrizes Brasileiras de Hipertensão Arterial – 2020
Barroso, W. K. S., Rodrigues, C. I. S., Bortolotto, L. A., Mota-Gomes, M. A., Brandão, A. A., Feitosa, A. D. D. M., Machado, C. A., Poli-de-Figueiredo, C. E., Amodeo, C., Mion, D., et al. (2021) · Arquivos Brasileiros de Cardiologia · doi:10.36660/abc.20201238 · Cited by 1,068
Molecular mechanisms of diabetic cardiomyopathy
Bugger, H., & Abel, E. D. (2014) · Diabetologia · doi:10.1007/s00125-014-3171-6 · Cited by 903
Basic Mechanisms of Diabetic Heart Disease
Ritchie, R. H., & Abel, E. D. (2020) · Circulation Research · doi:10.1161/circresaha.120.315913 · Cited by 708
Huynh, K., Bernardo, B. C., McMullen, J. R., & Ritchie, R. H. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.01.003 · Cited by 553
Russo, I., & Frangogiannis, N. G. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.12.011 · Cited by 474
Metadata
- Authors
- Singh, V. P., Le, B., Khode, R., Baker, K. M., & Kumar, R.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-12-01
- Volume
- 57
- Issue
- 12
- Pages
- 3297-3306
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2112333460
- Cited by
- 332
- References
- 54
- FWCI
- 14.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
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