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Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice.

American journal of physiology. Endocrinology and metabolism (2013-03-07)
Kavaljit H Chhabra, Huijing Xia, Kim Brint Pedersen, Robert C Speth, Eric Lazartigues
ABSTRACT

An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7-8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving β-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid β-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS.

MATERIALS
Product Number
Brand
Product Description

Roche
Liberase TL Research Grade, low Thermolysin concentration
Sigma-Aldrich
Angiotensin Converting Enzyme from rabbit lung, ≥2.0 units/mg protein (modified Warburg-Christian)
Sigma-Aldrich
Angiotensin Converting Enzyme from porcine kidney, lyophilized powder, ≥10 units/mg protein (Bradford)

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