Lipid peroxidation products reduce lysosomal protease activities in human retinal pigment epithelial cells via two different mechanisms of action

Krohne, Tim U.; Kaemmerer, Elke; Holz, Frank G.; Kopitz, Jürgen

doi:10.1016/j.exer.2009.10.014

Cited by 82 publications

(49 citation statements)

References 31 publications

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“…These oxidized lipids are known to increase lipofuscin production in RPE leading to photo‐sensibilization 45, inhibition of lysosomal enzymes 70 leading to an inhibition of autophagy and to an ageing of the RPE cells, all features found in AMD 71.…”

Section: Discussionmentioning

confidence: 99%

Effects of white light‐emitting diode (LED) exposure on retinal pigment epithelium in vivo

Jaadane

Rodriguez

Boulenguez

et al. 2017

J Cellular Molecular Medi

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Ageing and alteration of the functions of the retinal pigment epithelium (RPE) are at the origin of lost of vision seen in age‐related macular degeneration (AMD). The RPE is known to be vulnerable to high‐energy blue light. The white light‐emitting diodes (LED) commercially available have relatively high content of blue light, a feature that suggest that they could be deleterious for this retinal cell layer. The aim of our study was to investigate the effects of “white LED” exposure on RPE. For this, commercially available white LEDs were used for exposure experiments on Wistar rats. Immunohistochemical stain on RPE flat mount, transmission electron microscopy and Western blot were used to exam the RPE. LED‐induced RPE damage was evaluated by studying oxidative stress, stress response pathways and cell death pathways as well as the integrity of the outer blood–retinal barrier (BRB). We show that white LED light caused structural alterations leading to the disruption of the outer blood–retinal barrier. We observed an increase in oxidized molecules, disturbance of basal autophagy and cell death by necrosis. We conclude that white LEDs induced strong damages in rat RPE characterized by the breakdown of the BRB and the induction of necrotic cell death.

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Section: Discussionmentioning

confidence: 99%

Effects of white light‐emitting diode (LED) exposure on retinal pigment epithelium in vivo

Jaadane

Rodriguez

Boulenguez

et al. 2017

J Cellular Molecular Medi

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“…Furthermore, covalent adduction and modification of amino acid residues have been shown to be involved in the inactivation of cysteine Cats in response to electrophilic stressors (including singlet oxygen, nitroxyl, and reactive carbonyl species). [19] CatL activity is also inhibited by singlet oxygen. [20] Moreover, CatL inactivation can be antagonized by the thiol antioxidant N -acetyl-l-cysteine.…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet A Enhances Cathepsin L Expression and Activity via JNK Pathway in Human Dermal Fibroblasts

Zheng

Chen

et al. 2016

Chinese Medical Journal

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Background:Cathepsin L (CatL) is a cysteine protease with strong matrix degradation activity that contributes to photoaging. Mannose phosphate-independent sorting pathways mediate ultraviolet A (UVA)-induced alternate trafficking of CatL. Little is known about signaling pathways involved in the regulation of UVA-induced CatL expression and activity. This study aims to investigate whether a single UVA irradiation affects CatL expression and activity and whether mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) pathway is involved in the regulation of UVA-induced CatL expression and activity in human dermal fibroblasts (HDFs).Methods:Primary HDFs were exposed to UVA. Cell proliferation was determined by a cell counting kit. UVA-induced CatL production and activity were studied with quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and fluorimetric assay in cell lysates collected on three consecutive days after irradiation. Time courses of UVA-activated JNK and p38MAPK signaling were examined by Western blotting. Effects of MAPK inhibitors and knockdown of Jun and Fos on UVA-induced CatL expression and activity were investigated by RT-PCR, Western blotting, and fluorimetric assay. Data were analyzed by one-way analysis of variance.Results:UVA significantly increased CatL gene expression, protein abundance, and enzymatic activity for three consecutive days after irradiation (F = 83.11, 56.14, and 71.19, respectively; all P < 0.05). Further investigation demonstrated phosphorylation of JNK and p38MAPK activated by UVA. Importantly, inactivation of JNK pathway significantly decreased UVA-induced CatL expression and activity, which were not affected by p38MAPK inhibition. Moreover, knockdown of Jun and Fos significantly attenuated basal and UVA-induced CatL expression and activity.Conclusions:UVA enhances CatL production and activity in HDFs, probably by activating JNK and downstreaming AP-1. These findings provide a new possible molecular approach for antiphotoaging therapy.

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“…The accumulation of lipofuscin is a hallmark of RPE senescence and it is a major factor in lysosomal dysfunction (Holz et al, 1999; Bergmann et al, 2004). With lipofuscin accumulation, both phagocytotic capacity (heterophagy) and processes associated ith degradation of damaged mtDNA and cytoplasmic proteins via autophagy may become disturbed, which subsequently leads to increased transcytosis and exocytosis of proteins and drusen formation outside RPE cells (Krohne et al, 2010; Viiri et al, 2013; Kaarniranta et al, 2013; Kay et al, 2014; Kim et al, 2013; Valapala et al, 2014b; Sundelin et al, 1998). …”

Section: 0 Dysregulation Of Clearance Systems: Progression From Parmentioning

confidence: 99%

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Ferrington

Sinha

Kaarniranta

2016

Progress in Retinal and Eye Research

190

221

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Maintenance of protein homeostasis, also referred to as “Proteostasis”, integrates multiple pathways that regulate protein synthesis, folding, translocation, and degradation. Failure in proteostasis may be one of the underlying mechanisms responsible for the cascade of events leading to age-related macular degeneration (AMD). This review covers the major degradative pathways (ubiquitin-proteasome and lysosomal involvement in phagocytosis and autophagy) in the retinal pigment epithelium (RPE) and summarizes evidence of their involvement in AMD. Degradation of damaged and misfolded proteins via the proteasome occurs in coordination with heat shock proteins. Evidence of increased content of proteasome and heat shock proteins in retinas from human donors with AMD is consistent with increased oxidative stress and extensive protein damage with AMD. Phagocytosis and autophagy share key molecules in phagosome maturation as well as degradation of their cargo following fusion with lysosomes. Phagocytosis and degradation of photoreceptor outer segments ensures functional integrity of the neural retina. Autophagy rids the cell of toxic protein aggregates and defective mitochondria. Evidence suggesting a decline in autophagic flux includes the accumulation of autophagic substrates and damaged mitochondria in RPE from AMD donors. An age-related decrease in lysosomal enzymatic activity inhibits autophagic clearance of outer segments, mitochondria, and protein aggregates, thereby accelerating the accumulation of lipofuscin. This cumulative damage over a person’s lifetime tips the balance in RPE from a state of para-inflammation, which strives to restore cell homeostasis, to the chronic inflammation associated with AMD.

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Lipid peroxidation products reduce lysosomal protease activities in human retinal pigment epithelial cells via two different mechanisms of action

Cited by 82 publications

References 31 publications

Effects of white light‐emitting diode (LED) exposure on retinal pigment epithelium in vivo

Effects of white light‐emitting diode (LED) exposure on retinal pigment epithelium in vivo

Ultraviolet A Enhances Cathepsin L Expression and Activity via JNK Pathway in Human Dermal Fibroblasts

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

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