Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

Vähätupa, Maria; Järvinen, Tero; Uusitalo‐Järvinen, Hannele

doi:10.3389/fphar.2020.00873

Cited by 37 publications

(36 citation statements)

References 119 publications

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“…The murine model of fluctuating oxygen is most representative of human ROP ( Hartnett and Penn, 2012 ). Vähätupa et al recently used the OIR mouse model to discover new therapeutic drug targets in retinopathies using a novel mass spectrometric technique and sequential window acquisition of all theoretical fragment ion mass spectra in genetically modified mouse strains ( Vahatupa et al, 2020 ). ROP is almost exclusively a disease found in premature infants.…”

Section: Discussionmentioning

confidence: 99%

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model

Jiang

Luo

et al. 2021

Front. Pharmacol.

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Objectives: Probenecid is an anion transport inhibitor, which, according to the connectivity map (CMap; a biological application database), interferes with hypoxia-induced gene expression changes in retinal vascular endothelial cells (ECs). Here, we investigated the influence of probenecid on retinal EC cytotoxicity and retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model.Methods: The retinal EC growth rate in the presence of hypoxia-mimicking concentrations of cobalt chloride (CoCl2) was determined using the thiazolyl blue tetrazolium bromide (MTT) assay and proliferating cell nuclear antigen (PCNA) expression. In OIR rats, probenecid was administered by intraperitoneal injection (i.p.) from postnatal day (P) 1 to P7. The concentrations of vitreous humor vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, and placental growth factor (PlGF) were determined by using the ELISA kit at P21. The amount of newly formed vascular lumen was evaluated by histopathological examination. Retinopathy and neovascularization were assessed by scoring isolectin B4 fluorescein–stained retinal flat mounts. Western blots for liver tissue HIF-1α and hepcidin (HAMP) were performed.Results:In vitro, probenecid led to the recession of the hypoxia-induced EC growth rate. In vivo, compared to the OIR retina, the upregulation of VEGF, HIF-1α, and PlGF in phase II retinopathy of prematurity (ROP) was inhibited by probenecid administration. Moreover, probenecid ameliorated neovascularization and resulted in significantly reduced relative leakage fluorescence signal intensity in fluorescein-stained retinal flat mounts (p < 0.05). Probenecid alleviated the liver overactivation of HAMP and downregulation of HIF-1α in OIR rats.Conclusions: This is the first demonstration that implies that probenecid might be a protective compound against retinal angiogenesis in OIR. These changes are accompanied with decreased hyperoxia-mediated hepcidin overproduction. Although the relevance of the results to ROP needs further research, these findings may help establish potential pharmacological targets based on the CMap database.

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Section: Discussionmentioning

confidence: 99%

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model

Jiang

Luo

et al. 2021

Front. Pharmacol.

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“…Further evidence of UDCA therapeutic potential was seen in our recent study of ROP, a leading cause of preventable blindness in children [103,104]. We investigated the efficacy of the secondary bile acid, UDCA and its taurine and glycine conjugated derivatives TUDCA and glycoursodeoxycholic acid (GUDCA) in preventing retinal neovascularization (RNV) in an experimental model of ROP.…”

Section: Pharmacological Effects Of Bile Acids In Ocular Diseasementioning

confidence: 99%

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

et al. 2021

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Bile acids (BAs) are amphipathic sterols primarily synthesized from cholesterol in the liver and released in the intestinal lumen upon food intake. BAs play important roles in micellination of dietary lipids, stimulating bile flow, promoting biliary phospholipid secretion, and regulating cholesterol synthesis and elimination. Emerging evidence, however, suggests that, aside from their conventional biological function, BAs are also important signaling molecules and therapeutic tools. In the last decade, the therapeutic applications of BAs in the treatment of ocular diseases have gained great interest. Despite the identification of BA synthesis, metabolism, and recycling in ocular tissues, much remains unknown with regards to their biological significance in the eye. Additionally, as gut microbiota directly affects the quality of circulating BAs, their analysis could derive important information on changes occurring in this microenvironment. This review aims at providing an overview of BA metabolism and biological function with a focus on their potential therapeutic and diagnostic use for retinal diseases.

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“…Hypoxia driven retinal neovascularization is a key feature in devastating ischemic retinal diseases such as proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) [1,2]. Abnormal angiogenesis is associated with vascular leakage, hemorrhages and fibrovascular proliferation, which result in retinal edema, retinal/vitreous hemorrhages or tractional retinal detachments and subsequent loss of vision.…”

Section: Introductionmentioning

confidence: 99%

“…There is also evidence suggesting that the anti-VEGF treatment does not reverse the pathologic process of non-perfusion in DR [13]. Furthermore, anti-VEGFs may lose their therapeutic effect in slowing down the progression of the retinopathy [1,3]. There are also side effects related to the dosing of anti-VEGF compounds.…”

Section: Introductionmentioning

confidence: 99%

Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR)

et al. 2021

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Pathological angiogenesis is the hallmark of ischemic retinal diseases among them retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and a widely used model for ischemic retinopathies. We explored whether the vascular homing peptide CAR (CARSKNKDC) which recognizes angiogenic blood vessels can be used to target the retina in OIR. We were able to demonstrate that the systemically administered CAR vascular homing peptide homed selectively to the preretinal neovessels in OIR. As a cell and tissue-penetrating peptide, CAR also penetrated into the retina. Hyperoxia used to induce OIR in the retina also causes bronchopulmonary dysplasia in the lungs. We showed that the CAR peptide is not targeted to the lungs in normal mice but is targeted to the lungs after hyperoxia-/hypoxia-treatment of the animals. The site-specific delivery of the CAR peptide to the pathologic retinal vasculature and the penetration of the retinal tissue may offer new opportunities for treating retinopathies more selectively and with less side effects.

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Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

Cited by 37 publications

References 119 publications

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR)

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