TY - JOUR
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.
N1 - Funding Information:
We thank Dr. K. Islam, Dr. K. Kitada, J. Minas, A. Masuda, M. Seki, and M. Carter. This work was partially supported by National Heart, Lung, and Blood Institute (NHLBI) Grant R01-HL-091767 to R. M. Ortiz, NIH Grants P01-HL-051971 and P20-GM-104357 to University of Mississippi Medical Center-Physiology, American Heart Association Grant-in-Aid GIA2060203, Veterans Affairs Merit Award BX002604-01A2, and NHLBI Grant HL-136684-A0 to M. J. Ryan. A. Lee, R. Rodriguez, and B. Martinez were supported in part by National Institute on Minority Health and Health Disparities Grant 9T37-MD-001480. B. Martinez was supported by the Dennis R. Washington Graduate Achievement Scholarship.
Funding Information:
This work was partially supported by National Heart, Lung, and Blood Institute (NHLBI) Grant R01-HL-091767 to R. M. Ortiz, NIH Grants P01-HL-051971 and P20-GM-104357 to University of Mississippi Medical Center-Physiology, American Heart Association Grant-in-Aid GIA2060203, Veterans Affairs Merit Award BX002604-01A2, and NHLBI Grant HL-136684-A0 to M. J. Ryan. A. Lee, R. Rodriguez, and B. Martinez were supported in part by National Institute on Minority Health and Health Disparities Grant 9T37-MD-001480. B. Martinez was supported by the Dennis R. Washington Graduate Achievement Scholarship.
Publisher Copyright:
© 2018. American Physiological Society. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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.
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.
KW - Hypertension
KW - Inflammation
KW - Insulin resistance
KW - Metabolic syndrome
KW - Renin-angiotensin system
UR - http://www.scopus.com/inward/record.url?scp=85056556185&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00156.2018
DO - 10.1152/ajprenal.00156.2018
M3 - Article
C2 - 29993275
AN - SCOPUS:85056556185
SN - 0363-6127
VL - 315
SP - F1081-F1090
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 4
ER -