Abstract
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.
Highlights
Major morbidities associated with diabetes include adverse cardiovascular events and nephropathy, a leading cause of end-stage renal disease [1]
Since proteinuria predicts adverse renal outcomes and its reduction is associated with improved kidney function [35], we evaluated whether the AT1R antagonist candesartan, in an intermediate- to ultra-high dose range, reduces renal injury in db/db mice, a model of type 2 diabetes
We sought to address this by studying the putative role of the protective axis of the renin–angiotensin system (RAS), by focusing on angiotensin-converting enzyme 2 (ACE2), angiotensin II (Ang II) type 2 receptor (AT2R) and Mas, in a mouse model of diabetic nephropathy treated with increasing doses of candesartan, from intermediate (1 mg/kg/d) to ultra-high doses
Summary
Major morbidities associated with diabetes include adverse cardiovascular events and nephropathy, a leading cause of end-stage renal disease [1]. Effects of candesartan on RAS receptor expression in kidney cortex In vehicle-treated groups, db/db mice displayed increased expression of AT2R compared with db/ + mice (Figure 5a). Protein expression of AT2R (a) and Mas receptor (b) in kidney cortex from db/ + and db/db mice treated with vehicle or candesartan (1, 5, 25 or 75 mg/kg/d).
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