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.
Highlights
Angiotensin-converting enzyme (ACE) 2, a homolog of ACE and a newly discovered member of the renin-angiotensin system (RAS) [1,2], is expressed predominantly in the endothelium of intrarenal vessels and in renal tubular epithelium [2]
Eight wks after STZ administration, diabetic rats were further randomly divided into five groups (n = 10 in each group): no treatment group that served as a diabetic control group, adenoviral-mediated ACE2 gene transfer (Ad-ACE2) group that received an intravenous injection of adenovirus-carried murine ACE2 gene at a dose of 4 × 1010 plaque-forming units, Ad-green flurescent protein (GFP) group that received an intravenous injection of adenovirus-carried green fluorescent protein at a dose of 4 × 1010 pfu, ACE inhibition (ACEI) group that received benazepril given by intra-gastric intubation at a dose of 10 mg · kg–1 · d–1 [24]; and Ad-ACE2 + ACEI group that received a combined Ad-ACE2 and benazepril treatment as described above
The major finding of the present study was that, in a rat model of diabetic nephropathy, ACE2 gene transfection effectively reduced systolic blood pressure (SBP), urinary albumin excretion, creatinine clearance (Ccr) and glomeruli sclerosis index (GSI), and these beneficial effects were similar to ACEI treatment
Summary
Angiotensin-converting enzyme (ACE) 2, a homolog of ACE and a newly discovered member of the renin-angiotensin system (RAS) [1,2], is expressed predominantly in the endothelium of intrarenal vessels and in renal tubular epithelium [2]. The tissue-specific expression of ACE2, and its unique cleavage of the key vasoactive peptide Ang II, suggest an essential role of ACE2 in the local RAS of the heart and kidney [2]. The role of ACE2 in the modulation of cardiovascular function has been investigated by deliberate genetic manipulation, including targeted disruption [5,6] and overexpression [7,8,9], and these studies have consistently demonstrated that ACE2 has beneficial effects of antihypertension, antifibrosis and antiatherosclerosis. Blockade of RAS by ACE inhibition (ACEI) and Ang II receptor antagonists is currently the standard
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