Key result
Higher Ace gene copy number accelerates diabetic mesangial expansion by ~28% in mice.
Why the study?
Does increased Ace gene dosage modulate the renal renin-angiotensin system and worsen diabetic nephropathy in mice with STZ-induced diabetes?
Does increased Ace gene dosage modulate the renal renin-angiotensin system and worsen diabetic nephropathy in mice with STZ-induced diabetes?
An increased number of Ace gene copies in the setting of diabetes exacerbates diabetic nephropathy by generating a disruptive imbalance in the renal renin-angiotensin system, including paradoxically high levels of Ang-(1-7) and bradykinin.
Answers are grounded in this paper and cite their sources.
Ace copy number variation may modulate diabetic nephropathy in mice; hypothesis-generating and should not yet change clinical practice.
Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1-7). Increased concentration of renal Ang-(1-7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication.
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Bertoncello et al. (2015) studied Diabetic nephropathy in a preclinical model. Increased Ace gene dosage (3 copies) combined with STZ-induced diabetes vs. Mice with 1 copy of the Ace gene and/or non-diabetic controls was evaluated on PAS-positive relative mesangial matrix area at 12 weeks (p=<0.05). Mice with 3 copies of the Ace gene and diabetes demonstrated accelerated mesangial expansion compared to 1-copy diabetic mice, associated with increased renal Ang II, Ang-(1-7), and bradykinin.
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