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

Ruben Rodriguez, Andrew Lee, Keisa W. Mathis, Hanna J. Broome, Max Thorwald, Bridget Martinez, Daisuke Nakano, Akira Nishiyama, Michael J. Ryan, Rudy M. Ortiz

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)F1081-F1090
JournalAmerican journal of physiology. Renal physiology
Volume315
Issue number4
DOIs
StatePublished - 1 Oct 2018

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Angiotensin Receptors
Glucose Intolerance
Tumor Necrosis Factor-alpha
Blood Pressure
Angiotensin Type 1 Receptor
Inflammation
Angiotensin Receptor Antagonists
Adiposity
Glucose
Amlodipine
Calcium Channel Blockers
Renin-Angiotensin System
Albumins
Triglycerides
Hypertension
Kidney

Keywords

  • hypertension
  • inflammation
  • insulin resistance
  • metabolic syndrome
  • renin-angiotensin system

Cite this

Rodriguez, Ruben ; Lee, Andrew ; Mathis, Keisa W. ; Broome, Hanna J. ; Thorwald, Max ; Martinez, Bridget ; Nakano, Daisuke ; Nishiyama, Akira ; Ryan, Michael J. ; Ortiz, Rudy M. / Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats. In: American journal of physiology. Renal physiology. 2018 ; Vol. 315, No. 4. pp. F1081-F1090.
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Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats. / Rodriguez, Ruben; Lee, Andrew; Mathis, Keisa W.; Broome, Hanna J.; Thorwald, Max; Martinez, Bridget; Nakano, Daisuke; Nishiyama, Akira; Ryan, Michael J.; Ortiz, Rudy M.

In: American journal of physiology. Renal physiology, Vol. 315, No. 4, 01.10.2018, p. F1081-F1090.

Research output: Contribution to journalArticle

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T1 - Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats

AU - Rodriguez, Ruben

AU - Lee, Andrew

AU - Mathis, Keisa W.

AU - Broome, Hanna J.

AU - Thorwald, Max

AU - Martinez, Bridget

AU - Nakano, Daisuke

AU - Nishiyama, Akira

AU - Ryan, Michael J.

AU - Ortiz, Rudy M.

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AB - 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.

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KW - inflammation

KW - insulin resistance

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