Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice

Niu, Ming-Jia; Yang, Jin‐Kui; Lin, Shanshan; Ji, Xiu-Juan; Guo, Limin

doi:10.1007/s12020-008-9110-x

Cited by 100 publications

(94 citation statements)

References 32 publications

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“…The importance of AT 1 R and ACE2 in the regulation of glycemia has been demonstrated previously by our group (3) and others (11,25,28,35,40).…”

Section: E881supporting

confidence: 63%

“…ACE2 plays a significant role in glucose homeostasis. ACE2-knockout mice exhibit impaired glucose tolerance and insulin resistance compared with age-matched wild-type littermates (4,28). In addition, recently, our laboratory has demonstrated the beneficial effects of ACE2 gene therapy on glucose regulation and ␤-cell function in diabetic db/db mice (3), a genetic model of obesity-induced diabetes.…”

mentioning

confidence: 99%

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

Chhabra

Xia

Pedersen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Chhabra KH, Xia H, Pedersen KB, Speth RC, Lazartigues E. Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice. Am J Physiol Endocrinol Metab 304: E874-E884, 2013. First published March 5, 2013; doi:10.1152/ajpendo.00490.2012.-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 ␤-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 ␤-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS.angiotensin II; angiotensin-converting enzyme 2; angiotensin II type 1 receptor; type 2 diabetes mellitus; ␤-cell dysfunction; oxidative stress ANGIOTENSIN II (Ang II), a key component of the renin-angiotensin system (RAS), plays a pivotal role in mediating insulin resistance (15,16,18,33) and impaired glucose tolerance (27), thereby contributing to the development of type 2 diabetes mellitus (T2DM). Several clinical trials have explored the benefits of RAS blockade in controlling T2DM. A recent meta-analysis by Tocci et al. (41) showed that angiotensinconverting enzyme (ACE) inhibitors or Ang II type 1 receptor (AT 1 R) blockers reduce the risk for new-onset T2DM in individuals with hypertension or an elevated risk for cardiovascular events. In light of these beneficial effects, agents that counteract or block the RAS may have a potential for treatment of T2DM. ACE2 is a carboxypeptidase that converts Ang II to Ang-(1-7), whose signaling opposes that of Ang II. ACE2 thus provides a compensatory mechanism to counter...

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“…The importance of AT 1 R and ACE2 in the regulation of glycemia has been demonstrated previously by our group (3) and others (11,25,28,35,40).…”

Section: E881supporting

confidence: 63%

mentioning

confidence: 99%

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

Chhabra

Xia

Pedersen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Nevertheless, whether ACE2 activation improves peripheral insulin resistance is still unknown. Although ACE2 deficiency induces or exacerbates vascular inflammation, heart failure, atherosclerosis, and renal damage in pathological conditions (19,35,38,39,54,55), the EDRs in aortas and the capacity of ROS production in primary cultured mouse endothelial cells and the plasma Ang (1-7) level are not different between ACE2 wild-type and deficient mice on normal chow. Moreover, the pharmacological inhibition of ACE2-Ang (1-7) did not impair EDRs in aortas from normal mice.…”

Section: Discussionmentioning

confidence: 93%

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

Zhang

Liu

Luo

et al. 2015

Antioxidants & Redox Signaling

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Aims: Angiotensin-converting enzyme 2 (ACE2)-angiotensin (1-7) [Ang (1-7)]-Mas constitutes the vasoprotective axis and is demonstrated to antagonize the vascular pathophysiological effects of the classical reninangiotensin system. We sought to study the hypothesis that upregulation of ACE2-Ang (1-7) signaling protects endothelial function through reducing oxidative stress that would result in beneficial outcome in diabetes. Results: Ex vivo treatment with Ang (1-7) enhanced endothelium-dependent relaxation (EDR) in renal arteries from diabetic patients. Both Ang (1-7) infusion via osmotic pump (500 ng/kg/min) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection (10 9 pfu/mouse) rescued the impaired EDR and flow-mediated dilatation (FMD) in db/db mice. Diminazene aceturate treatment (15 mg/kg/day) activated ACE2, increased the circulating Ang (1-7) level, and augmented EDR and FMD in db/db mouse arteries. In addition, activation of the ACE2-Ang (1-7) axis reduced reactive oxygen species (ROS) overproduction determined by dihydroethidium staining, CM-H 2 DCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortas and also in high-glucose-treated endothelial cells. Pharmacological benefits of ACE2-Ang (1-7) upregulation on endothelial function were confirmed in ACE2 knockout (ACE2 KO) mice both ex vivo and in vitro. Innovation: We elucidate that the ACE2-Ang (1-7)-Mas axis serves as an important signal pathway in endothelial cell protection in diabetic mice, especially in diabetic human arteries. Conclusion: Endogenous ACE2-Ang (1-7) activation or ACE2 overexpression preserves endothelial function in diabetic mice through increasing nitric oxide bioavailability and inhibiting oxidative stress, suggesting the therapeutic potential of ACE2-Ang(1-7) axis activation against diabetic vasculopathy. Antioxid. Redox Signal. 23, 880-892.

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“…Male Ace2 KO mice displayed a selective decrease in first-phase insulin secretion in response to glucose and a progressive impairment of glucose tolerance compared with wildtype mice [122]. Mice lacking ACE2 also exhibit accelerated diabetic nephropathy with increased urinary albumin excretion, mesangial matrix scores, and glomerular basement membrane thicknesses [123].…”

Section: Angiotensin-converting Enzymementioning

confidence: 99%

The Renin Angiotensin System and the Metabolic Syndrome~!2010-02-12~!2010-04-19~!2010-06-25~!

Wang¹,

Li²,

Takahashi³

2010

TOHYPERJ

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Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice

Cited by 100 publications

References 32 publications

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

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

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

The Renin Angiotensin System and the Metabolic Syndrome~!2010-02-12~!2010-04-19~!2010-06-25~!

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