Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 315, Issue 4, Pages F1081-F1090Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00156.2018
Keywords
hypertension; inflammation; insulin resistance; metabolic syndrome; renin-angiotensin system
Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI) [R01-HL-091767]
- NIH [P01-HL-051971, P20-GM-104357]
- American Heart Association [GIA2060203]
- Veterans Affairs Merit Award [BX002604-01A2]
- NHLBI [HL-136684-A0]
- National Institute on Minority Health and Health Disparities [9T37-MD-001480]
- Dennis R. Washington Graduate Achievement Scholarship
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Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-alpha (TNF-alpha) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-alpha inhibitor + angiotensin receptor blocker (ETAN + ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN + ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN + ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation.
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