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

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.

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“…In addition, ARBs have been reported to be able to use the ACE2/AT2R/Mas axis to ameliorate inflammation. 19 , 20 These additional effects of ARBs may result in the differences with ACEis with regards to the risk and outcomes of severe exacerbations and pneumonia in patients with COPD.…”

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“…47 Candesartan is renoprotective in intermediate doses in diabetic mice by upregulating ACE2/AT2R/Mas axis protective components. 48 In addition, olmesartan treatment in hypertensive patients resulted in increase of ACE2 expression in urine thus providing renoprotective effects. 34 Iwanami 49 et al studied the impact of treatment with azilsartan and olmesartan which are angiotensin II type 1 (AT1) receptor blockers in transgenic mice with the human renin and angiotensinogen genes (hRN/hANG-Tg) and found that azilsartan decreases blood pressure and increases sodium concentration in urine more than that of olmesartan with activation of ACE2/Ang-(1-7)/Mas axis.…”

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

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