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

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...

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Autores principales: Callera, Glaucia E., Antunes, Tayze T., Correa, Jose W., Moorman, Danielle, Gutsol, Alexey, He, Ying, Cat, Aurelie Nguyen Dinh, Briones, Ana M., Montezano, Augusto C., Burns, Kevin D., Touyz, Rhian M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091470/
https://www.ncbi.nlm.nih.gov/pubmed/27612496
http://dx.doi.org/10.1042/BSR20160344
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author Callera, Glaucia E.
Antunes, Tayze T.
Correa, Jose W.
Moorman, Danielle
Gutsol, Alexey
He, Ying
Cat, Aurelie Nguyen Dinh
Briones, Ana M.
Montezano, Augusto C.
Burns, Kevin D.
Touyz, Rhian M.
author_facet Callera, Glaucia E.
Antunes, Tayze T.
Correa, Jose W.
Moorman, Danielle
Gutsol, Alexey
He, Ying
Cat, Aurelie Nguyen Dinh
Briones, Ana M.
Montezano, Augusto C.
Burns, Kevin D.
Touyz, Rhian M.
author_sort Callera, Glaucia E.
collection PubMed
description 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.
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spelling pubmed-50914702016-11-08 Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis Callera, Glaucia E. Antunes, Tayze T. Correa, Jose W. Moorman, Danielle Gutsol, Alexey He, Ying Cat, Aurelie Nguyen Dinh Briones, Ana M. Montezano, Augusto C. Burns, Kevin D. Touyz, Rhian M. Biosci Rep Original Papers 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. Portland Press Ltd. 2016-10-27 /pmc/articles/PMC5091470/ /pubmed/27612496 http://dx.doi.org/10.1042/BSR20160344 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution Licence 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Papers
Callera, Glaucia E.
Antunes, Tayze T.
Correa, Jose W.
Moorman, Danielle
Gutsol, Alexey
He, Ying
Cat, Aurelie Nguyen Dinh
Briones, Ana M.
Montezano, Augusto C.
Burns, Kevin D.
Touyz, Rhian M.
Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis
title Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis
title_full Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis
title_fullStr Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis
title_full_unstemmed Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis
title_short Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis
title_sort differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ace2/at2r/mas axis
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091470/
https://www.ncbi.nlm.nih.gov/pubmed/27612496
http://dx.doi.org/10.1042/BSR20160344
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