Angiotensin-Converting Enzyme 2 (ACE2) Activator Diminazene Aceturate Ameliorates Endotoxin-Induced Uveitis in Mice

Qiu, Yiguo; Shil, Pollob; Zhu, Ping; Yang, Hongxia; Verma, Amrisha; Lei, Bo; Li, Qiuhong

doi:10.1167/iovs.14-13883

Cited by 73 publications

(64 citation statements)

References 48 publications

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“…The severity of inflammation was graded blindly according to a previously reported scoring system [4] (Table 1). …”

Section: Methodsmentioning

confidence: 99%

“…The inflammation can compromise both the anterior and posterior segments of the eye. Endotoxin-induced uveitis (EIU) is an animal model widely used to study acute ocular inflammation, including uveitis, and can be established by the systemic or topical application of lipopolysaccharide (LPS), a component of the Gram-negative bacterial outer membrane [3, 4]. During uveitis, the blood–ocular barrier (BOB) can be disrupted and inflammatory cells, such as macrophages and neutrophils, infiltrate the eye [5, 6].…”

Section: Introductionmentioning

confidence: 99%

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Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lipocalin 2 (LCN2), an important mediator of a variety of cellular processes, is involved in regulating the inflammatory response, but its roles in different inflammatory diseases are controversial. Because the role of LCN2 in ocular inflammation has been unclear until now, we explored the function of LCN2 in lipopolysaccharide (LPS)-induced ocular inflammation in vivo and in vitro. Methods: Endotoxin-induced uveitis (EIU) was induced in male Sprague Dawley rats by the intravitreal injection of LPS. The expression and location of LCN2 in the retina were detected with western blotting and immunohistochemistry, respectively. We determined the clinical scores for anterior inflammation, quantified the infiltrated inflammatory cells, and measured the pro-inflammatory factors to determine the anti-inflammatory effects of LCN2 in EIU eyes. Cultured primary rat Müller cells were stimulated with LPS and the expression and secretion of LCN2 were measured with real-time PCR, western blotting, and an ELISA. After Müller cells were cotreated with LPS and LCN2 or PBS, the expression and secretion of TNF-α, IL-6, and MCP-1 were examined with realtime PCR, western blotting, and ELISAs. Western blotting and immunofluorescence were used to detect the phosphorylation and cellular distribution of nuclear factor kappaB (NF-κB) subunit p65. Results: In EIU, the expression of LCN2 was significantly upregulated in the retina, especially in the outer nuclear layer (mainly composed of Müller cells). LPS stimulation of cultured Müller cells also markedly elevated LCN2 expression. Intravitreal injection of LCN2 significantly reduced the clinical scores, inflammatory infiltration, and protein leakage in EIU, which correlated with the reduced levels of proinflammatory factors in the aqueous humor and retina. LCN2 treatment also reduced the expression and secretion of TNF-α, IL-6, and MCP-1 in LPS-stimulated Müller cells. LCN2 inhibited the inflammatory response by inhibiting the phosphorylation and translocation of NF-κB p65. Conclusions: LCN2 protects against ocular inflammation, at least in part, by negatively regulating the activation of the NF-κB signaling pathway. LCN2 may be a promising anti-inflammatory therapy for ocular diseases, such as uveitis.

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“…The severity of inflammation was graded blindly according to a previously reported scoring system [4] (Table 1). …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

Tang

et al. 2018

Cell Physiol Biochem

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“…Our previous study showed that activating ACE2 significantly reduced the CD45 þ macrophages in EIU mouse retina. 34 Similarly, AAVmediated intravitreal delivery of ACE2 decreased the retinal CD11b þ microglia cells in an animal model of DR. 55 In addition, our most recent study showed that AAV8-mediated activation of the ACE2/Ang-(1-7)/Mas axis confers a protective effect on were increased in the Ab1-42 group when compared with the untreated group and the Ab42-1 group. All data are expressed as mean 6 SEM (**P < 0.01, *P < 0.05, n ¼ 4).…”

Section: Ace2 Reduces Ab-induced Inflammation In Human Rpementioning

confidence: 97%

“…21,31,32 Our previous study showed that activation of ACE2 alleviated the lipopolysaccharide (LPS)-induced inflammatory response in both human RPE cells 33 and in endotoxin-induced uveitis (EIU) mouse/rat models. 34,35 Moreover, the most recent study from our laboratory demonstrated that adeno-associated virus (AAV)-mediated ACE2 gene delivery alleviated the ocular inflammation in experimental autoimmune uveitis (EAU) mouse model by activating the local ACE2/Ang-(1-7)/Mas axis. 36 However, it is unknown whether overexpression of ACE2 could ameliorate Ab-induced inflammatory responses, which is associated with the pathogenesis of a devastating common eye condition AMD.…”

Section: 20mentioning

confidence: 99%

“…29,52-54 ACE2 acts as a counter regulator of ACE in cleaving Ang II into Ang-(1-7), and exerts beneficial effects in several animal models of ocular diseases, including DR, 55 glaucoma, 56 EIU, 34,35 and EAU. 21,36 On the other hand, ACE2 deletion exaggerated Ang II-induced expressions of inflammatory cytokines.…”

Section: Ace2 Reduces Ab-induced Inflammation In Human Rpementioning

confidence: 99%

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Overexpression of Angiotensin-Converting Enzyme 2 Ameliorates Amyloid β-Induced Inflammatory Response in Human Primary Retinal Pigment Epithelium

Lin

Qiu

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Overexpression of angiotensin-converting enzyme 2 ameliorates amyloid b-induced inflammatory response in human primary retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2017;58:3018-3028. DOI:10.1167/ iovs.17-21546 PURPOSE. Amyloid-b (Ab) is a major constituent of drusen, which is a hallmark of early AMD. The purpose of this study was to investigate whether enhancement of ACE2, an important component of the protective angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas axis of the renin angiotensin system (RAS), ameliorates Ab-induced inflammatory response in human RPE cells. METHODS.Annexin-V FITC/propidium iodide assay for detecting apoptosis rate was used to determine the optimum concentration and incubation time of Ab1-42. ACE2 plasmid was transfected into primary cultured human RPE (hRPE) and ARPE-19 cells for 6 hours followed by stimulation with Ab1-42 at the concentration of 1 lM for 48 hours. Gene expression was detected by real-time PCR and protein levels were determined by Western blotting or ELISA. A779, an antagonist of Ang-(1-7), was used to further confirm the involvement of ACE2/Ang-(1-7)/Mas axis. RESULTS.Flow cytometry showed that the optimal concentration of Ab1-42 was 1 lM and the optimal incubation time was 48 hours. Ab1-42 upregulated the expression of IL-1b and monocyte chemoattractant protein-1. ACE2 plasmid significantly upregulated the expression of ACE2 and Ang-(1-7) in hRPE and ARPE-19 cells. Activation of ACE2 reduced the overproduction of inflammatory cytokines at both mRNA and protein levels in hRPE and ARPE-19 cells stimulated with Ab1-42. Furthermore, an antagonist of Ang-(1-7), A779 reversed the anti-inflammatory effect of ACE2.CONCLUSIONS. Overexpression of ACE2 ameliorates Ab-induced inflammatory response by activating the ACE2/Ang-(1-7)/Mas axis in human RPE cells. Our data suggest that ACE2/Ang-(1-7)/Mas axis may be a promising target for developing novel therapies for inflammation response in AMD.

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Elevated YKL‐40 serum levels may contribute to wet age‐related macular degeneration via the ERK1/2 pathway

et al. 2021

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Angiotensin-Converting Enzyme 2 (ACE2) Activator Diminazene Aceturate Ameliorates Endotoxin-Induced Uveitis in Mice

Abstract: Endogenous ACE2 activation by DIZE has a preventive effect on LPS-induced ocular inflammation in the EIU mouse model. These results support the notions that RAS plays a role in modulating ocular immune response and that enhancing ACE2 provides a novel therapeutic strategy for uveitis.

Cited by 73 publications

References 48 publications

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

Overexpression of Angiotensin-Converting Enzyme 2 Ameliorates Amyloid β-Induced Inflammatory Response in Human Primary Retinal Pigment Epithelium

Elevated YKL‐40 serum levels may contribute to wet age‐related macular degeneration via the ERK1/2 pathway

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