Differential renal effects of candesartan at high-and ultra-high doses in diabetic mice: potential role of  ACE2/AT2R/Mas

Callera, G. et al. (2016) Differential renal effects of candesartan at high-and ultra-high doses in diabetic mice: potential role of  ACE2/AT2R/Mas. Bioscience Reports, 36(5), e00398. (doi: 10.1042/BSR20160344) (PMID:27612496) (PMCID:PMC5091470)

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High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Briones, Dr Ana and Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Touyz, Professor Rhian
Authors: Callera, G., Antunes, T., Correa, J., Moorman, D., Gutsol, A., He, Y., Nguyen Dinh Cat, A., Briones, A. M., Montezano, A. C., Burns, K., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Bioscience Reports
Publisher:Portland Press Ltd.
ISSN (Online):1573-4935
Published Online:08 September 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Bioscience Reports 36(5):e00398
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES