Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats.

Abstract

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-α (TNF-α) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-α 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.

• Authors: Ruben Rodriguez, Andrew Lee, Keisa W Mathis, Hanna J Broome, Max Thorwald, Bridget Martinez, Daisuke Nakano, Akira Nishiyama, Michael J Ryan, Rudy M Ortiz
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 315 Issue 4 Pg. F1081-F1090 (10 01 2018) ISSN: 1522-1466 [Electronic] United States
• PMID: 29993275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiotensin Receptor Antagonists
• Blood Glucose
• Receptor, Angiotensin, Type 1
• Tumor Necrosis Factor-alpha

Topics

• Angiotensin Receptor Antagonists (pharmacology)
• Animals
• Blood Glucose (metabolism)
• Blood Pressure (drug effects)
• Glucose Intolerance (metabolism)
• Hypertension (metabolism)
• Insulin Resistance (physiology)
• Male
• Metabolic Syndrome (drug therapy, metabolism)
• Obesity (metabolism)
• Rats, Long-Evans
• Receptor, Angiotensin, Type 1 (metabolism)
• Renin-Angiotensin System (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)