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- Title
Activation of the Renin Angiotensin System Causes High Blood Pressure in (db/db) Diabetic Mice.
- Authors
Senador, Danielle; Kanakamedala, Keerthy; Zhang, Wenfeng; Chen, Yanfang; Morris, Mariana; Elased, Khalid M.
- Abstract
Cardiovascular disease is a long term complication of diabetes, which remains a leading cause of mortality and morbidity. The goal of this study was to study the role of renin angiotensin system (RAS) in the control of cardiovascular function in the db/db model of type 2 diabetes. Mice (7-8 weeks) were implanted with carotid telemetric probes and 24 hr mean arterial pressure (MAP), heart rate (HR) and activity was monitored weekly up to 15 weeks. At an early age (8-10 weeks), db/db mice developed significant hyperglycemia and hyperinsulinemia which was not associated with changes in MAP. By 12 weeks MAP in diabetics was higher as compared to their lean controls both during day (101 ± 1 vs 117 ± 2 mmHg, p<0.01, n=6) and night (110 ± 1.7 vs 121 ± 3.1 mmHg, p<0.01). Chronic treatment with losartan (10 mg/kg/day, drinking water) for 12 weeks significantly blocked the progression of the increased MAP in diabetic mice during day (102 ± 4 vs 117 ± 2.5 mmHg, p<0.01) and night (104 ± 4 vs 126 ± 2.2 mmHg, p<0.01), comparing db/db control to losartan treated. An enzyme assay using Surface Enhanced Laser Desorption/ Ionization Mass Spectrometry (SELDI-TOF-MS) evaluated plasma RAS activity. Plasma aliquots (1 µl) from 14 week normal and db/db-diabetic mice were added to buffer spiked with Ang I (1296, M/Z) and incubated for 2 hours at 37°C. ProteinChips (CM 10) were spotted with the reaction mixture and analyzed using MS. Results demonstrated the formation of a peak corresponding to Ang II (1045, M/Z) indicating angiotensin converting enzyme (ACE I) activity. There was no MS peak corresponding to Ang 1-7 (899, M/Z), indicating no detectable plasma ACE2. There was a significant increase in plasma ACE1 activity in db/db-diabetics as compared to controls (p<0.05). Results document: 1) increase of MAP db/db diabetic mice, 2) importance of Ang AT1 receptors and plasma ACE1 in mediating the blood pressure changes in this model of type 2 diabetes and 3) potential for using SELDI-TOF-MS to study the RAS and processing of angiotensin peptides.
- Subjects
RENIN-angiotensin system; HYPERTENSION; DIABETES complications; TYPE 2 diabetes; ANGIOTENSIN converting enzyme; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA377
- ISSN
0012-1797
- Publication type
Article