High doses of AngII receptor (AT1R) blockers (ARBs) are reno-protective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) upregulate 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 versus 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 upregulating 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.
- renin angiotensin system
- angiotensin receptor blockers
- blood pressure
- ©2016 The Author(s)
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