Abstract 229: Increased Ace Gene Dosage Reduces Ace2 Activity in Diabetic Mice Kidney: Involvement of Ace/ace2 Balance on the Development of Diabetic Nephropathy
Abstract only The mechanisms underlying the link between high constitutive levels of ACE and diabetic nephropathy has not been completely understood, but an imbalance between angiotensin I (ACE) and II (ACE2) converting enzymes homeostasis has been described in diabetic kidney disease. The aim of th...
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Published in | Hypertension (Dallas, Tex. 1979) Vol. 62; no. suppl_1 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.09.2013
|
Online Access | Get full text |
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Summary: | Abstract only
The mechanisms underlying the link between high constitutive levels of ACE and diabetic nephropathy has not been completely understood, but an imbalance between angiotensin I (ACE) and II (ACE2) converting enzymes homeostasis has been described in diabetic kidney disease. The aim of this study was to evaluate ACE/ACE2 homeostasis in kidney from diabetic mice presenting increased dosage of ACE gene. Male mice (3 months old) genetically engineered to harbor one or three copies of the
ACE
gene were made diabetic (streptozotocin - STZ, 50 mg/Kg) and randomly assigned into: 1-copy control (1CC), 1-copy diabetic (1CD), 3-copy control (3CC) and 3-copy diabetic. At the end of experimental period body weight was evaluated and kidney was excised. Kidney-to-body weight ratio and ACE and ACE 2 activities were determined using specific substrates (ZPhe-HL and 7-Mca-APK(Dnp), respectively) (Two way ANOVA + Tukey test; P<0.05). Diabetes increased blood glucose (1CD : 436 ± 25
vs.
1CC: 90 ± 2; 3CD: 556 ± 6
vs.
3CC: 112 ± 4 mg/dL) and kidney-to-body weight ratio (1CD: 7.5 ± 0.2
vs.
1CC: 5.8 ± 0.2; 3CD: 7.8 ± 0.1
vs.
3CC: 5.8 ± 0.1 mg/g) with no influence of
ACE
genotype. As expected, renal ACE activity was directly related to
ACE
gene copy number in control group (3CC: 9.4 ± 2.11
vs.
1CC:5.6 ± 0.9 mU/mg protein). Renal ACE activity was decreased in diabetic groups (1CD: 3.6 ± 0.2
vs.
1CC: 5.6 ± 0.9; 3CD: 2.3 ± 0.4
vs.
3CC: 9.4 ± 2.1 mU/mg protein) with no influence of
ACE
genotype. Under physiological condition, renal ACE2 activity remained unchanged regardless of the
ACE
genotype (1CC: 1.9 ± 0.2 = 3CC: 1.4 ± 0.1 μM/min/mg). However upon a pathological stimulus, renal ACE2 activity was efficiently increased only in 1CD group, but not in 3CD, as compared with the others (1CD: 5.1 ± 0.9 vs. 1CC: 1.9 ± 0.2 = 3CC: 1.4 ± 0.1 = 3CD: 2.2 ± 0.2 μM/min/mg). Taken together, our results show for the first time, that susceptibility for the development of diabetic nephropathy associated with increased ACE gene dosage may be, at least in part, caused by a decrease on renal ACE2 activity. This may result in increased local levels of angiotensin II and decreased angiotensin (1-7), leading to altered glomerular permeability and albuminuria, functional alterations presented by 3CD animals. Financial Support: FAPESP, CAPES, CNPq. |
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ISSN: | 0194-911X 1524-4563 |
DOI: | 10.1161/hyp.62.suppl_1.A229 |