Key result
Diabetic mice with three copies of the ACE gene developed significantly higher urinary albumin excretion (380 µg/24h) and blood pressure compared to those with one or two copies, demonstrating that modestly increased ACE levels cause diabetic nephropathy.
Why the study?
Does a genetically increased ACE level cause nephropathy and increased blood pressure in diabetic mice?
Does a genetically increased ACE level cause nephropathy and increased blood pressure in diabetic mice?
A modest genetic increase in ACE levels is sufficient to cause overt nephropathy and increased blood pressure in diabetic mice.
ACE gene dosage modulates nephropathy in diabetic mice; leaves open human causality and therapeutic targeting.
Diabetic nephropathy is a major risk factor for end-stage renal disease and cardiovascular diseases and has a marked genetic component. A common variant (D allele) of the angiotensin I-converting enzyme (ACE) gene, determining higher enzyme levels, has been associated with diabetic nephropathy. To address causality underlying this association, we induced diabetes in mice having one, two, or three copies of the gene, normal blood pressure, and an enzyme level range (65-162% of wild type) comparable to that seen in humans. Twelve weeks later, the three-copy diabetic mice had increased blood pressures and overt proteinuria. Proteinuria was correlated to plasma ACE level in the three-copy diabetic mice. Thus, a modest genetic increase in ACE levels is sufficient to cause nephropathy in diabetic mice.
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Huang et al. (2001) studied Diabetic nephropathy (n=47). Three copies of the ACE gene (genetically increased ACE level) vs. One or two copies of the ACE gene was evaluated on Urinary albumin excretion at 12 weeks (µg/24h) (p=<0.0001). Diabetic mice with three copies of the ACE gene developed significantly higher urinary albumin excretion (380 µg/24h) and blood pressure compared to those with one or two copies, demonstrating that modestly increased ACE levels cause diabetic nephropathy.
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