Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes

Lee, Sik; Kim, Won; Moon, Sang-Ok; Sung, Mi Jeong; Kim, Duk Hoon; Kang, Kyung Pyo; Jang, Kyu Yoon; Lee, Sang Yong; Park, Byung Hyun; Koh, Gou Young; Park, Sung Kwang

doi:10.1093/ndt/gfl598

Cited by 68 publications

(58 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In our present H 2 O 2 -induced acute lung injury model, NF-κB levels in nuclear protein extracts were substantially increased, showing that NF-κB is activated and administration of COMP-Ang1 suppressed NF-κB activation induced by H 2 O 2 -inhalation. These findings are consistent with previous reports that Ang1/Tie2 signaling inhibits upregulation of NF-κB activity (Hughes et al, 2003;Lee et al, 2007). Together, we suggest that one likely mechanism of H 2 O 2 -mediated increase in vascular permeability is upregulation of VEGF gene expression by NF-κB activation and that COMP-Ang1-mediated reduction of vascular permeability and VEGF expression is partly due to inhibition of NF-κB activation.…”

Section: Discussionsupporting

confidence: 93%

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

et al. 2008

View full text Add to dashboard Cite

Abbreviations: Ang1, angiopoietin-1; BAL, bronchoalveolar lavage; COMP, cartilage oligomeric matrix protein; EBD, Evans blue dye; HIF, hypoxia inducible factor; ICAM-1, intercellular adhesion molecule-1; p-Akt, phosphorylated Akt; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidyl inositol-3,4,5-triphosphate; ROS, reactive oxygen species; Rrs, respiratory system resistance; Tie2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2; VCAM-1, vascular cell adhesion molecule-1 AbstractReactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP-Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-α, IL-1β, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1α (HIF-1α) and NF-κB in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H 2 O 2 . We have also found that the activation of HIF-1α and NF-κB and the increase of phosphoinositide 3-kinase activity in lung tissues after H 2 O 2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.

show abstract

Section: Discussionsupporting

confidence: 93%

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

et al. 2008

View full text Add to dashboard Cite

show abstract

“…In addition, the modulating effects of angiopoietins on inflammation, alluded to previously, may also be relevant to glomerulonephritides; however, to explore further the possible roles of angiopoietins in glomerular disease, one will have to manipulate their levels in these same models. In this regard, some promising data were reported by Lee et al,56 who demonstrated that systemic delivery of cartilage oligomeric matrix proteinAng-1 (COMP-Ang-1; a modified form of Ang-1) by adenoviral transduction of hepatocytes reduced renal fibrosis in db/db mice, a model of type 2 diabetes; however, this strategy also caused significant improvement in hyperglycemia, which could itself, at least partly, account for the amelioration of diabetes.…”

Section: Angiopoietin Expression In Acquired Glomerular Diseasementioning

confidence: 99%

Roles of Angiopoietins in Kidney Development and Disease

Woolf

Gnudi

Long

2009

Journal of the American Society of Nephrology

114

View full text Add to dashboard Cite

“…Most recent studies have demonstrated that the systemic administration of Ang-1 significantly reduced cardiac hypertrophy and myocardial fibrosis in phenylephrine-induced cardiac hypertrophy (45). Furthermore, overexpression of Ang-1 decreased transforming growth factor-1␤ expression and attenuated interstitial fibrosis progression in the kidneys of db/db mice (46). Consistent with these findings, our present study showed that Ang-1 gene therapy resulted in significant decreases in both myocardial fibrosis and in the heart weight-to-body weight ratio (hypertrophy) following myocardial ischemia in db/db mice, implicating the favorable effects of Ang-1 gene therapy on myocardial ischemia-induced adverse remodeling.…”

Section: Ang-1 Rescues Impaired Angiogenesis In Diabetesmentioning

confidence: 99%

Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice

Chen

Stinnett

2008

Diabetes

View full text Add to dashboard Cite

OBJECTIVE— Diabetic impaired angiogenesis is associated with impairment of hypoxia-inducible factor-1α (HIF-1α) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1α stabilization and vascular maturation in db/db mice. RESEARCH DESIGN AND METHODS— db/db mice were systemically administrated adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1α, vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), Akt, and HIF-1α–prolyl-4-hydroxylase-2 (PHD)2 expression were measured. Vasculature maturation, capillary and arteriole densities, and cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium. RESULTS— Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1α stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db/db mice compared with wild-type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1α signaling. CONCLUSIONS— Normalization of immature vasculature by Ang-1 gene therapy may represent a novel therapeutic strategy for treatment of the diabetes-associated impairment of myocardial angiogenesis.

show abstract

Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes

Abstract: We conclude that COMP-Ang1 delayed the fibrotic changes in the kidney of diabetic db/db mice through its anti-inflammatory or metabolic effects.

Cited by 68 publications

References 20 publications

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

Roles of Angiopoietins in Kidney Development and Disease

Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice

Contact Info

Product

Resources

About