Diabetic Retinopathy in the Spontaneously Diabetic Torii Rat: Pathogenetic Mechanisms and Preventive Efficacy of Inhibiting the Urokinase-Type Plasminogen Activator Receptor System

被引:30
作者
Cammalleri, Maurizio [1 ]
Dal Monte, Massimo [1 ]
Locri, Filippo [1 ]
Marsili, Stefania [1 ]
Lista, Liliana [2 ]
De Rosa, Mario [3 ]
Pavone, Vincenzo [2 ]
Rusciano, Dario [4 ]
Bagnoli, Paola [1 ]
机构
[1] Univ Pisa, Dept Biol, Via San Zeno 31, I-56127 Pisa, Italy
[2] Univ Napoli Federico II, Dept Biol, Via Cinthia,Edificio 7, I-80126 Naples, Italy
[3] Second Univ Napoli, Dept Expt Med, Via Santa Maria di Costantinopoli 16, I-80138 Naples, Italy
[4] Sooft Fidia Pharma, Contrada Molino 17, I-63833 Montegiorgio, Italy
关键词
BLOOD-RETINAL BARRIER; ENDOTHELIAL GROWTH-FACTOR; PEPTIDE UPARANT; MOLECULAR-MECHANISMS; ANIMAL-MODELS; KAPPA-B; INFLAMMATION; EXPRESSION; CELLS; ANGIOGENESIS;
D O I
10.1155/2017/2904150
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
The spontaneously diabetic Torii (SDT) rat is of increasing preclinical interest because of its similarities to human type 2 diabetic retinopathy (DR). The system formed by urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is a player in blood-retinal barrier (BRB) breakdown in DR. Here, we investigated whether in SDT rats, preventive administration of UPARANT, an inhibitor of the uPAR pathway, counteracts the retinal impairment in response to chronic hyperglycemia. Electroretinogram (ERG) monitoring was followed over time. Fluorescein-dextran microscopy, CD31 immunohistochemistry, quantitative PCR, ELISA, Evans blue perfusion, and Western blot were also used. UPARANT prevented ERG dysfunction, upregulation of vascular endothelial growth factor and fibroblast growth factor-2, BRB leakage, gliosis, and retinal cell death. The mechanisms underlying UPARANT benefits were studied comparing them with the acute streptozotocin (STZ) model in which UPARANT is known to inhibit DR signs. In SDT rats, but not in the STZ model, UPARANT downregulated the expression of uPAR and its membrane partners. In both models, UPARANT reduced the levels of transcription factors coupled to inflammation or inflammatory factors themselves. These findings may help to establish the uPAR system as putative target for the development of novel drugs that may prevent type 2 DR.
引用
收藏
页数:18
相关论文
共 46 条
[1]
Arbeláez-Quintero I, 2017, STROKE RES TREAT, V2017, DOI 10.1155/2017/9756429
[2]
Pathophysiology and treatment of diabetic retinopathy [J].
Bandello, Francesco ;
Lattanzio, Rosangela ;
Zucchiatti, Ilaria ;
Del Turco, Claudia .
ACTA DIABETOLOGICA, 2013, 50 (01) :1-20
[3]
Preclinical evaluation of the urokinase receptor-derived peptide UPARANT as an anti-inflammatory drug [J].
Boccella, Serena ;
Panza, Elisabetta ;
Lista, Liliana ;
Belardo, Carmela ;
Ianaro, Angela ;
De Rosa, Mario ;
de Novellis, Vito ;
Pavone, Vincenzo .
INFLAMMATION RESEARCH, 2017, 66 (08) :701-709
[4]
The Urokinase Receptor-Derived Peptide UPARANT Recovers Dysfunctional Electroretinogram and Blood-Retinal Barrier Leakage in a Rat Model of Diabetes [J].
Cammalleri, Maurizio ;
Locri, Filippo ;
Marsili, Stefania ;
Dal Monte, Massimo ;
Pisano, Claudio ;
Mancinelli, Angelo ;
Lista, Liliana ;
Rusciano, Dario ;
De Rosa, Mario ;
Pavone, Vincenzo ;
Bagnoli, Paola .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2017, 58 (07) :3138-3148
[5]
The Urokinase Receptor-Derived Peptide UPARANT Mitigates Angiogenesis in a Mouse Model of Laser-Induced Choroidal Neovascularization [J].
Cammalleri, Maurizio ;
Dal Monte, Massimo ;
Locri, Filippo ;
Lista, Liliana ;
Aronsson, Monica ;
Kvanta, Anders ;
Rusciano, Dario ;
De Rosa, Mario ;
Pavone, Vincenzo ;
Andre, Helder ;
Bagnoli, Paola .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2016, 57 (06) :2600-2611
[6]
UPARANT: A Urokinase Receptor-Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency [J].
Carriero, Maria Vincenza ;
Bifulco, Katia ;
Minopoli, Michele ;
Lista, Liliana ;
Maglio, Ornella ;
Mele, Luigi ;
Di Carluccio, Gioconda ;
De Rosa, Mario ;
Pavone, Vincenzo .
MOLECULAR CANCER THERAPEUTICS, 2014, 13 (05) :1092-1104
[7]
Expression and Signaling of Formyl-Peptide Receptors in the Brain [J].
Cattaneo, Fabio ;
Guerra, Germano ;
Ammendola, Rosario .
NEUROCHEMICAL RESEARCH, 2010, 35 (12) :2018-2026
[8]
Antiangiogenic Effectiveness of the Urokinase Receptor-Derived Peptide UPARANT in a Model of Oxygen-Induced Retinopathy [J].
Dal Monte, Massimo ;
Rezzola, Sara ;
Cammalleri, Maurizio ;
Belleri, Mirella ;
Locri, Filippo ;
Morbidelli, Lucia ;
Corsini, Michela ;
Paganini, Giuseppe ;
Semeraro, Francesco ;
Cancarini, Anna ;
Rusciano, Dario ;
Presta, Marco ;
Bagnoli, Paola .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2015, 56 (04) :2392-2407
[9]
Novel pharmacotherapies in diabetic retinopathy: Current status and what's in the horizon [J].
Das, Arup ;
McGuire, Paul G. ;
Monickaraj, Finny .
INDIAN JOURNAL OF OPHTHALMOLOGY, 2016, 64 (01) :4-13
[10]
Retinal Macroglial Responses in Health and Disease [J].
de Hoz, Rosa ;
Rojas, Blanca ;
Ramirez, Ana I. ;
Salazar, Juan J. ;
Gallego, Beatriz I. ;
Trivino, Alberto ;
Ramirez, Jose M. .
BIOMED RESEARCH INTERNATIONAL, 2016, 2016