MMP targeting in the battle for vision: Recent developments and future prospects in the treatment of diabetic retinopathy

Drankowska, Justyna; Kos, Michał; Kościuk, Andrzej; Marzęda, Paweł; Boguszewska-Czubara, Anna; Tylus, Magdalena; Święch-Zubilewicz, Anna

doi:10.1016/j.lfs.2019.05.038

Cited by 27 publications

(15 citation statements)

References 87 publications

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“…Basement membrane, a specialized ECM of microvessel and intermediate for EC-RMP communication, degrades generally with EC migration and invasion. MMPs, one of the major mediators of endothelial barrier degradation, have been shown to regulate the structure and function of ECM molecules under physiological and pathological processes [12][13][14][15][16]. The correlation between the expression of different MMPs and the presence of ECs and pericytes has also been suggested.…”

Section: Discussionmentioning

confidence: 99%

“…Matrix metalloproteinases (MMPs), one of the major mediators of barrier degradation, modulate the structure and function of ECM molecules under physiological and pathological processes [12][13][14]. The involvement of MMPs in iBRB disruption during diabetic retinopathy, retinal ischemia, and retinal neovascularization has been demonstrated in numerous studies [15][16][17]. The association between the expression levels of different MMPs and the presence of ECs and pericytes has also been suggested [18], but it has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity

et al. 2021

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Inner blood-retina barrier (iBRB) is primarily formed of retinal microvascular endothelial cells (ECs) with tight junctions, which are surrounded and supported by retinal microvascular pericytes (RMPs) and basement membrane. Pericytes are believed to be critically involved in the physiology and pathology of iBRB. However, the underlying mechanism remains to be fully elucidated. We developed a novel in vitro iBRB model which was composed of primary cultures of rat retinal ECs and RMPs based on Transwell system. We tested the involvement of pericytes in the migration and invasion of ECs, examined the expression and activity of matrix metalloproteinase- (MMP-) 2/MMP-9 in the culture, evaluated the TEER and permeability of iBRB, and assessed the expression of ZO-1, occludin, claudin-5, and VE-cadherin of endothelial junctions. We found that RMPs with indirect contact of ECs can increase the expression of MMP-2 and upgrade the activity of MMP-2/9 in the coculture, which subsequently decreased TJ protein abundance of ZO-1 and occludin in ECs, promoted the migration of ECs, and finally reduced the integrity of iBRB. Taken together, our data show that RMP relative location with ECs is involved in the integrity of iBRB via MMP-2/9 and has important implications for treating diabetic retinopathy and other retinal disorders involving iBRB dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity

et al. 2021

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“…Lastly, the extracellular matrix remodeling factor Mmp14 is reportedly a crucial regulator of cell stemness and vascular remodeling. 105 Studies have also implicated Mmp14a in retinal developmental processes such as RGC axon guidance and innervation of the optic tectum. [66][67][68] Future studies will assess the functional implication of Atoh7-mediated downregulation of mmp14a during vascular-retinal development.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of the zebrafishatoh7−/−Mutant,lakritz, highlights Atoh7‐dependent genetic networks with potential implications for human eye diseases

et al. 2020

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Expression of the bHLH transcription protein Atoh7 is a crucial factor conferring competence to retinal progenitor cells for the development of retinal ganglion cells. Several studies have emerged establishing ATOH7 as a retinal disease gene. Remarkably, such studies uncovered ATOH7 variants associated with global eye defects including optic nerve hypoplasia, microphthalmia, retinal vascular disorders, and glaucoma. The complex genetic networks and cellular decisions arising downstream of atoh7 expression, and how their dysregulation cause development of such disease traits remains unknown. To begin to understand such Atoh7‐dependent events in vivo, we performed transcriptome analysis of wild‐type and atoh7 mutant ( lakritz ) zebrafish embryos at the onset of retinal ganglion cell differentiation. We investigated in silico interplays of atoh7 and other disease‐related genes and pathways. By network reconstruction analysis of differentially expressed genes, we identified gene clusters enriched in retinal development, cell cycle, chromatin remodeling, stress response, and Wnt pathways. By weighted gene coexpression network, we identified coexpression modules affected by the mutation and enriched in retina development genes tightly connected to atoh7 . We established the groundwork whereby Atoh7‐linked cellular and molecular processes can be investigated in the dynamic multi‐tissue environment of the developing normal and diseased vertebrate eye.

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“…Activation of MMP-2 and MMP-9 is important in pathogenesis of diabetic microangiopathic complications such as diabetic retinopathy, nephropathy, and neuropathy [39]. Diabetic retinopathy, by inducing apoptosis of retinal endothelial cells and by degrading the junction proteins, is followed by increased vascular permeability [80,81]. In experimental models of DM, increased oxidative stress activates MMP-2, and antioxidant therapies inhibit the development of diabetic retinopathy by modulating retinal MMP-2 levels [32,82].…”

Section: Egcg Effect On Matrix Metalloproteinasesmentioning

confidence: 99%

The Effect of Nano-Epigallocatechin-Gallate on Oxidative Stress and Matrix Metalloproteinases in Experimental Diabetes Mellitus

et al. 2020

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Background: The antioxidant properties of epigallocatechin-gallate (EGCG), a green tea compound, have been already studied in various diseases. Improving the bioavailability of EGCG by nanoformulation may contribute to a more effective treatment of diabetes mellitus (DM) metabolic consequences and vascular complications. The aim of this study was to test the comparative effect of liposomal EGCG with EGCG solution in experimental DM induced by streptozotocin (STZ) in rats. Method: 28 Wistar-Bratislava rats were randomly divided into four groups (7 animals/group): group 1—control group, with intraperitoneal (i.p.) administration of 1 mL saline solution (C); group 2—STZ administration by i.p. route (60 mg/100 g body weight, bw) (STZ); group 3—STZ administration as before + i.p. administration of EGCG solution (EGCG), 2.5 mg/100 g b.w. as pretreatment; group 4—STZ administration as before + i.p. administration of liposomal EGCG, 2.5 mg/100 g b.w. (L-EGCG). The comparative effects of EGCG and L-EGCG were studied on: (i) oxidative stress parameters such as malondialdehyde (MDA), indirect nitric oxide (NOx) synthesis, and total oxidative status (TOS); (ii) antioxidant status assessed by total antioxidant capacity of plasma (TAC), thiols, and catalase; (iii) matrix-metalloproteinase-2 (MMP-2) and -9 (MMP-9). Results: L-EGCG has a better efficiency regarding the improvement of oxidative stress parameters (highly statistically significant with p-values < 0.001 for MDA, NOx, and TOS) and for antioxidant capacity of plasma (highly significant p < 0.001 for thiols and significant for catalase and TAC with p < 0.05). MMP-2 and -9 were also significantly reduced in the L-EGCG-treated group compared with the EGCG group (p < 0.001). Conclusions: the liposomal nanoformulation of EGCG may serve as an adjuvant therapy in DM due to its unique modulatory effect on oxidative stress/antioxidant biomarkers and MMP-2 and -9.

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MMP targeting in the battle for vision: Recent developments and future prospects in the treatment of diabetic retinopathy

Cited by 27 publications

References 87 publications

Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity

Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity

Transcriptome analysis of the zebrafishatoh7−/−Mutant,lakritz, highlights Atoh7‐dependent genetic networks with potential implications for human eye diseases

The Effect of Nano-Epigallocatechin-Gallate on Oxidative Stress and Matrix Metalloproteinases in Experimental Diabetes Mellitus

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