scholarly journals Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway

2017 ◽  
Author(s):  
Rosario Fernandez-Godino ◽  
Kinga M. Bujakowska ◽  
Eric A. Pierce
Keyword(s):  
Extracellular Matrix ◽  
Macular Degeneration ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Alternative Complement Pathway ◽  
Complement C3 ◽  
Matrix Metalloproteinase 2 ◽  
Complement Pathway ◽  
Rpe Cells ◽  
Alternative Complement

ABSTRACTThe design of efficient therapies for age-related macular degeneration (AMD) is limited by our understanding of the pathogenesis of basal deposits, which form between retinal pigment epithelium (RPE) and Bruch’s membrane (BrM) early in disease, and involve activation of the complement system. To investigate the roles of BrM, RPE and complement in AMD, we generated ARPE-19 cells with the p.R345W mutation in EFEMP1, which causes early-onset macular degeneration. The ARPE-19-EFEMP1R345W/R345W cells make abnormal extracellular matrix (ECM) that binds active complement C3 and causes the formation of basal deposits by normal human fetal (hf)RPE cells. hfRPE cells grown on abnormal ECM or BrM explants from AMD donors show chronic activation of the alternative complement pathway by excessive deposition of C3b. This process is exacerbated by impaired ECM turnover via increased matrix metalloproteinase-2 (MMP-2) activity. Therapies that target ECM synthesis and turnover and activation of C3 could be effective for early AMD.

scholarly journals Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium

2021 ◽  
Author(s):  
Abbi L. Engel ◽  
YeKai Wang ◽  
Thomas Khuu ◽  
Emily Worrall ◽  
Megan A Manson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Macular Degeneration ◽  
Retinal Pigment ◽  
Critical Role ◽  
Thick Layer ◽  
Age Related Macular Degeneration ◽  
Calcium Deposition ◽  
Breakdown Product ◽  
Metabolomics Data ◽  
Age Related

Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD). SFD results from mutations found in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. TIMP3 is secreted by the retinal pigmented epithelium (RPE) into the underlying Bruch's membrane (BrM), and it plays a critical role in maintaining extracellular matrix (ECM) homeostasis. A characteristic feature of post-mortem SFD globes is a thick layer of sub-RPE deposits overlying a disorganized BrM. Although likely central to the pathogenesis of SFD, no animal models have reproduced this phenotype. We generated induced pluripotent stem cell (iPSC)-derived RPE lines from SFD family members with the S204C TIMP3 mutation and observed that SFD RPE have highly dysregulated ECM and form large basal deposits by ~30 days in culture. The sub-RPE deposits are similar in ultrastructure and composition when compared to SFD family member globes. Mutant TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in the reversal of sub-RPE calcium deposition. We found that SFD TIMP3 has decreased inhibition of secreted matrix metalloproteinases. ECM dysfunction substantially impacts cellular metabolism. Targeted metabolomics data showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE. Further, SFD RPE also has decreased intracellular reduced glutathione and is more vulnerable to oxidative stress. These findings suggest that key elements of SFD pathology can be recapitulated in culture which may lead to insights into disease mechanisms and potential treatments.

scholarly journals Dietary Polyphenols in Age-Related Macular Degeneration: Protection against Oxidative Stress and Beyond

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Elzbieta Pawlowska ◽  
Joanna Szczepanska ◽  
Ali Koskela ◽  
Kai Kaarniranta ◽  
Janusz Blasiak
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Retinal Pigment ◽  
Janus Kinase ◽  
Age Related Macular Degeneration ◽  
Hydroxyl Groups ◽  
Ros Scavenging ◽  
Rpe Cells ◽  
Dietary Polyphenols ◽  
Age Related

Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by degeneration and loss of photoreceptors and retinal pigment epithelium (RPE) cells with oxidative stress playing a role in its pathology. Although systematic reviews do not support the protective role of diet rich in antioxidants against AMD, dietary polyphenols (DPs) have been reported to have beneficial effects on vision. Some of them, such as quercetin and cyanidin-3-glucoside, can directly scavenge reactive oxygen species (ROS) due to the presence of two hydroxyl groups in their B ring structure. Apart from direct ROS scavenging, DPs can lower oxidative stress in several other pathways. Many DPs induce NRF2 (nuclear factor, erythroid 2-like 2) activation and expression of phase II enzymes that are under transcriptional control of this factor. DPs can inhibit A2E photooxidation in RPE cells, which is a source of oxidative stress. Anti-inflammatory action of DPs in RPE cells is associated with regulation of various interleukins and signaling pathways, including IL-6/JAK2 (Janus kinase 2)/STAT3. Some DPs can improve impaired cellular waste clearance, including AMD-specific deficient phagocytosis of the Aβ42 peptide and autophagy.

scholarly journals Protective Effects of Curcumin Ester Prodrug, Curcumin Diethyl Disuccinate against H2O2-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells: Potential Therapeutic Avenues for Age-Related Macular Degeneration

2019 ◽  
Vol 20 (13) ◽  
pp. 3367 ◽  
Author(s):  
Chawanphat Muangnoi ◽  
Umar Sharif ◽  
Pahweenvaj Ratnatilaka Na Bhuket ◽  
Pornchai Rojsitthisak ◽  
Luminita Paraoan
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Retinal Pigment ◽  
Parent Drug ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Protective Effects ◽  
Rpe Cells ◽  
Age Related ◽  
Potent Drug

Oxidative stress-induced damage to the retinal pigmented epithelium (RPE), a specialised post-mitotic monolayer that maintains retinal homeostasis, contributes to the development of age-related macular degeneration (AMD). Curcumin (Cur), a naturally occurring antioxidant, was previously shown to have the ability to protect RPE cells from oxidative stress. However, poor solubility and bioavailability makes Cur a poor therapeutic agent. As prodrug approaches can mitigate these limitations, we compared the protective properties of the Cur prodrug curcumin diethyl disuccinate (CurDD) against Cur in relation to oxidative stress induced in human ARPE-19 cells. Both CurDD and Cur significantly decreased H2O2-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Both drugs exerted their protective effects through the modulation of p44/42 (ERK) and the involvement of downstream molecules Bax and Bcl-2. Additionally, the expression of antioxidant enzymes HO-1 and NQO1 was also enhanced in cells treated with CurDD and Cur. In all cases, CurDD was more effective than its parent drug against oxidative stress-induced damage to ARPE-19 cells. These findings highlight CurDD as a more potent drug compared to Cur against oxidative stress and indicate that its protective effects are exerted through modulation of key apoptotic and antioxidant molecular pathways.

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