Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Abstract

The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 mg/kg streptozotocin. Eight wks after streptozotocin injection, the diabetic rats were divided into no treatment group, adenoviral (Ad)-ACE2 group, Ad-green flurescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI group. Four wks after treatment, physical, biochemical, and renal functional and morphological parameters were measured. An experiment in cultured glomerular mesangial cells was performed to examine the effects of ACE2 on cellular proliferation, oxidative stress and collagen IV synthesis. In comparison with the Ad-GFP group, the Ad-ACE2 group exhibited reduced systolic blood pressure, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index and renal malondialdehyde level; downregulated transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefits. ACE2 transfection attenuated angiotensin (Ang) II-induced glomerular mesangial cell proliferation, oxidative stress and collagen IV protein synthesis. In conclusion, ACE2 exerts a renoprotective effect similar to that of ACEI treatment. Decreased renal Ang II, increased renal Ang-(1-7) levels, and inhibited oxidative stress were the possible mechanisms involved.

Angiotensin-converting enzyme 2 regulates renal atrial natriuretic peptide through angiotensin-(1–7)

“…Tikellis et al [10] have also demonstrated that ACE2 is decreased in the diabetic tubule. Consistent with this, ACE2 overexpression has been reported to have a renoprotective effect since it prevents experimental diabetic glomerular injury [11]. However, the mechanisms for a reduction in ACE2 being associated with kidney disease, including the progression of diabetic nephropathy, have still to be fully clarified.…”

“…For example, Shah et al [12] have demonstrated that the blockage of NPR-A in the heart diminished the antihypertrophic effect of Ang-(1-7). Interestingly, given the renoprotective paracrine effects of ANP [14][15][16]37], the finding that ACE2 increases ANP in vitro could also explain why overexpression of ACE2 in diabetic mice results in amelioration of their glomerular injury [11]. Thus we speculate that the benefit of reintroducing ACE2 in diabetic mice might partly be due to an expected increase in renal ANP levels.…”

Telmisartan acts through the modulation of ACE-2/ANG 1–7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis

“…Increased oxidative stress may contribute to LV remodeling and dysfunction in heart failure (Watanabe et al, 2006;Korantzopoulos et al, 2003). Recent study reported that local RAS was highly activated, as manifested by increased ACE expression and ANG-II level, and decreased ACE-2 expression and ANG 1-7 level in the heart (Liu et al, 2011). As the key peptide of the RAS, ANG-II exerts a variety of effects via its type 1 receptor, including vasoconstriction, sodium retention, cell proliferation and apoptosis, proinflammation and oxidative stress (Oudit et al, 2007).…”

Angiotensin-(1–7) attenuates high glucose-induced proximal tubular epithelial-to-mesenchymal transition via inhibiting ERK1/2 and p38 phosphorylation

“…A down-regulation of ACE2 is observed in diabetes (Wong et al, 2007) while, administration of Ang-(1-7) in diabetic rat reduced proteinuria and restored renal vascular responses (Benter et al, 2007). An ACE2 over-expression is observed to ameliorate (Liu et al, 2011). Currently, the effects of Ang-(1-7) in the kidney have not been fully understood and are still in debate.…”