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 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.
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Glaucia E
GE
Callera
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Tayze T
TT
Antunes
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Jose W
JW
Correa
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Danielle
D
Moorman
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Alexey
A
Gutsol
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Ying
Y
He
Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Canada G12 8TA.
Aurelie Nguyen Dinh
AN
Cat
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Ana M
AM
Briones
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Canada G12 8TA.
Augusto C
AC
Montezano
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Kevin D
KD
Burns
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Canada G12 8TA Rhian.Touyz@glasgow.ac.uk.
Rhian M
RM
Touyz
D057912:Angiotensin II Type 2 Receptor Blockers / Q000008:administration & dosage; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D001786:Blood Glucose; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics; D013777:Tetrazoles / Q000008:administration & dosage*
D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C081643:candesartan
RAS; albuminuria; candesartan; nephropathy; type 2 diabetes