Loss of Angiotensin-Converting Enzyme-2 (Ace2) Accelerates Diabetic Kidney Injury

Wong, D.; Oudit, Gavin Y.; Reich, Heather N.; Kassiri, Zamaneh; Zhou, Juhua; Liu, Qiao C.; Backx, Peter H.; Penninger, Josef; Herzenberg, Andrew M.; Scholey, James W.

doi:10.2353/ajpath.2007.060977

Cited by 241 publications

(253 citation statements)

References 47 publications

(52 reference statements)

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“…Our results showed that ACE2 overexpression and ACE inhibition had similar effects on reducing renal Ang II levels, increasing renal Ang-(1-7) levels and decreasing the number of proliferative cells and the protein expression levels of TGF-β1, VEGF, type IV collagen and nephrin in glomeruli after 4 weeks of treatment. An interesting finding of the present study was that ACE2 overexpression and ACE inhibition had no impact on elevated serum glucose levels in the diabetic rats, which was consistent with the results of Wong et al, who showed that glycemic control was not worsen by the loss of ACE2 in the Akita diabetic mode (20). These results indicated that the renal protective effects of ACE2 were not attributable to glycemic control.…”

Section: A C E 2 -A M E L I O R a T E D D I A B E T I C N E P H R O Psupporting

confidence: 92%

“…The high expression of ACE2 in the normal kidney (2) and the reduced expression of ACE2 in diabetic rats (16) and human kidney diseases (17,18) suggest an ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2, most investigators have focused on ACE2 inhibition and demonstrated that ACE2 deficiency aggravated glomerular injury in mice (19)(20)(21). A recent study found that intraperitoneal injection of human recombinant ACE2 slowed the progression of diabetic nephropathy in diabetic mice, although exogenous proteins may cause immunity reaction after injection, which shortens its half-life (22).…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Liu

Wang

et al. 2010

Mol Med

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The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 mg/kg streptozotocin. Eight wks after streptozotocin injection, the diabetic rats were divided into no treatment group, adenoviral (Ad)-ACE2 group, Ad-green flurescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI group. Four wks after treatment, physical, biochemical, and renal functional and morphological parameters were measured. An experiment in cultured glomerular mesangial cells was performed to examine the effects of ACE2 on cellular proliferation, oxidative stress and collagen IV synthesis. In comparison with the Ad-GFP group, the Ad-ACE2 group exhibited reduced systolic blood pressure, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index and renal malondialdehyde level; downregulated transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefits. ACE2 transfection attenuated angiotensin (Ang) II-induced glomerular mesangial cell proliferation, oxidative stress and collagen IV protein synthesis. In conclusion, ACE2 exerts a renoprotective effect similar to that of ACEI treatment. Decreased renal Ang II, increased renal Ang-(1-7) levels, and inhibited oxidative stress were the possible mechanisms involved.

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Section: A C E 2 -A M E L I O R a T E D D I A B E T I C N E P H R O Psupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Liu

Wang

et al. 2010

Mol Med

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“…This is consistent with recent findings that loss of ACE2 or inhibition of ACE2 promotes glomerular injury in association with up-regulation of ACE expression in type-1 diabetic mice. 30,31 Nevertheless, breakdown of this autoregulating pathway may be one mechanism of beneficial effects on hypertensive complications with ACE inhibitors and AT1 receptor antagonists.…”

Section: Adv-dn-mentioning

confidence: 99%

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Koka

Huang

Chung

et al. 2008

The American Journal of Pathology

256

247

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The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to upregulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage. The prevalence of hypertension is approximately 30% based on National Health and Nutrition Examination Survey data, 1 making it one of the most important risk factors for cardiovascular disease, the major cause of mortality in the United States.The recent discovery of the angiotensin II (Ang II) breakdown enzyme angiotensin I -converting enzyme (ACE)2 and alternative Ang II-generating pathways such as chymase, in addition to ACE, has increased the complexity of our understanding of Ang II generation and degradation in hypertension. 2,3 ACE2 is a breakdown enzyme responsible for the degradation of Ang II to Angiotensin 1-7 peptide. The later has vasodilatory properties and has its own unique receptor, the Mas receptor. 3 Emerging evidence shows that ACE2 plays an important role in negatively regulating hypertension. In rat models of hypertension, renal ACE2 mRNA and protein are decreased, although this could not be confirmed in human hypertensive nephropathy in a prior study. 4 Further, in rats treated with ACE inhibitors and angiotensin receptor blockers, an increase in local renal ACE2 activity is noted. 5,6 We have shown earlier that ACE is up-regulated in human diabetic nephropathy accompanied with hypertension, a condition associated with high Ang II levels. 7 Taken together, these findings suggest that there may be an alteration in the ACE/ACE2 balance in hypertension in a manner that favors increased Ang II generation (ie, upre...

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“…Thus, Ang 1-7 has become a key component of the RAS system due to its beneficial effects in the cardiovascular system. Although the pathophysiological significance of ACE2 in renal injury remains to be established, emerging evidence suggests that ACE2 deficiency leads to increases in intrarenal Ang II levels (Ribeiro Oliveira Ferrario, 2006;Oudit et al;Wolf & Ritz, 2005;Ye et al;2006). Thus, recently ACE2 has also been proposed as an acute biomarker of renal disease, considering that upregulation of ACE2, and the subsequent increase in Ang 1-7 levels, may be a compensatory response to protect against tissue injury.…”

Section: Ace2mentioning

confidence: 99%

“…Furthermore, animals with STZ-induced DN have decreased renal expression of ACE2 . In humans, biopsies from patients with DN showed a decrease in glomerular expression of ACE2, suggesting that a therapy increasing the activity of this enzyme can help in the future in the treatment of diabetic kidney disease (Wong et al;.…”

Section: Ras and Diabetesmentioning

confidence: 99%

Up-Regulation of Renin-Angiotensin System in Diabetes and Hypertension: Implications on the Development of Diabetic Nephropathy

Casarini¹,

Arita²,

Cunha³

et al. 2012

Diabetic Nephropathy

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Loss of Angiotensin-Converting Enzyme-2 (Ace2) Accelerates Diabetic Kidney Injury

Cited by 241 publications

References 47 publications

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Up-Regulation of Renin-Angiotensin System in Diabetes and Hypertension: Implications on the Development of Diabetic Nephropathy

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