Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration

Chuang, Jen-Zen; Yang, Nan; Nakajima, Nobuyuki; Otsu, Wataru; Fu, Chaowei; Yang, Howard H.; Lee, Maxwell P.; Akbar, Armaan F.; Badea, Tudor C.; Guo, Zhen; Nuruzzaman, Afnan; Hsu, Kuo-Shun; Dunaief, Joshua L.; Sung, Ching Hwa

doi:10.1038/s41467-021-27935-9

Cited by 25 publications

(13 citation statements)

References 83 publications

(94 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, DR animals had visual acuity changes i.e., decrease the in SFT value in the OMR test and increase in the number of errors in the PM test. Similar results were reported [47,48]. The retinal tissue biomarkers in DR-induced animals were altered i.e., increased level of LDH and NSE and decreased the level of catalase activity, in congruent with the findings of other studies [7,49].…”

Section: Discussionsupporting

confidence: 91%

Astaxanthin Ameliorates Diabetic Retinopathy in Swiss Albino Mice via Inhibitory Processes of Neuron-Specific Enolase Activity

Subramanian

Thirunavukkarasu²,

Muthuraman³

2022

Processes

View full text Add to dashboard Cite

Retinopathy is one of the most common complications of diabetes mellitus. Diabetic retinopathy (DR) occurs due to microvascular damage in retinal tissues provoked by high blood sugar levels. The available drugs for DR are limited. Astaxanthin (AST) has anti-hypertensive, anti-obesity, and anti-diabetic properties. However, the therapeutic effect of AST on DR remains elusive. The present study is designed to investigate the effects of AST on DR via inhibition of neuron-specific enolase (NSE) activity. DR was induced by the administration of streptozotocin (STZ, 35 mg/kg: intraperitoneal; and 20 μL of STZ: intravitreal) in mice. AST (10 and 20 mg/kg) was administered orally (p.o.) for 21 days. The DR associated visual changes were assessed at different time intervals via optokinetic motor response (OMR) and penta-maze (PM) tests. Blood glucose level as well as retinal catalase, lactate dehydrogenase (LDH), & neuron-specific enolase (NSE) were estimated. The reference drug i.e., dexamethasone (DEX, 10 mg/kg; p.o.) was administered for 21 days. The administration of AST showed significant ameliorative potential in DR. Hence, AST can be used as a natural medicine for the management of DR due to its potential antioxidant, anti-diabetic, and NSE inhibitory properties.

show abstract

Section: Discussionsupporting

confidence: 91%

Astaxanthin Ameliorates Diabetic Retinopathy in Swiss Albino Mice via Inhibitory Processes of Neuron-Specific Enolase Activity

Subramanian

Thirunavukkarasu²,

Muthuraman³

2022

Processes

View full text Add to dashboard Cite

show abstract

“…3E and 3F). Accumulation of lipofuscin-laden pigmented microglia/macrophages in the subretinal space have also been observed in other AMD mouse models [40][41][42] and aged WT mice. 43 Furthermore, complement activation in the RPE is another key feature of AMD in humans 44,45 and also found in some mouse models.…”

Section: Gpx4 Cko Mice Mimic Clinicopathological Features Of Human Amdmentioning

confidence: 64%

Retinal Pigment Epithelium-Specific Ablation of GPx4 in Adult Mice Recapitulates Key Features of Geographic Atrophy in Age-Related Macular Degeneration

Ueta,

Azuma,

Kobayashi

et al. 2024

Preprint

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population, particularly the late-stage of dry AMD known as geographic atrophy (GA), lacks effective treatment options. Genetic mouse models of AMD have revealed the significance of impaired lipid metabolism and anti-oxidative capacity in early/intermediate stage of AMD, but remains unclear in GA that severely damages visual function. Here, to investigate the potential relevance of peroxidized lipids in RPE for late-stage dry AMD, GPx4fl/fl mice underwent subretinal injections of RPE-specific AAV-Cre vector or control AAV vector. RPE-specific GPx4 deficiency led to rapid RPE degeneration resembling key features of late-stage dry AMD, including preceding RPE cell polarity, acrolein and malondialdehyde accumulation, photoreceptor loss, lipofuscin-laden subretinal melanophage infiltration, and complement activation. Treatment with α-tocopherol and ferrostatin-1 mitigated RPE degeneration, and shrunk mitochondria were observed in GPx4 deficient mice, suggesting involvement of ferroptosis. Unexpectedly, necrostatin-1s, an inhibitor of necroptosis, also ameliorated RPE degeneration, and activation of RIP3 and MLKL along with inactivation of caspase-8 was observed, indicating crosstalk between ferroptosis and necroptosis pathways. Our findings shed light on the intricate mechanisms underlying RPE degeneration in AMD and highlight GPx4/lipid peroxidation as potential therapeutic targets. RPE-specific ablation of GPx4 in mice provides a valuable tool for further elucidating the interplay between lipid peroxidation, cell death pathways, and AMD pathogenesis, offering new insights for preclinical research and therapeutic development targeting GA.

show abstract

“…CX3CR1 -deficient mice have been reported to show prolonged presence of microglial cells (MC) in the subretinal space suggesting excessive photoreceptor OS phagocytosis by subretinal MC which subsequently accumulated SDD (Chuang et al, 2022). In the current study, SDD close to EN was characteristically observed in Cldn1 deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice

Nakai,

Lee,

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

The early and intermediate age-related macular degeneration (AMD) is characterized by the presence of drusen and pigmentary abnormalities in the retinal pigment epithelial (RPE) cells which form the outer blood retinal barrier (oBRB). Fluid leakage through the disrupted oBRB from the choroid to the neural retina has been implicated in the pathogenesis of AMD, however; the molecular mechanisms still remain unclear. The family of four transmembrane proteins, claudins are known to form tight junctions (TJs) in the oBRB. Nonetheless, there are few reports showing how they function in the oBRBin vivo. We found that claudin-1 is dominantly expressed in TJs of the mouse RPE. To investigate the role of claudin-1 in the RPE, we generated RPE-specificCldn1conditional knockout mice (Best1-Cre+/-Cldn1flox/floxmice:Cldn1cKO mice). Deficiency ofCldn1led to age-related lipid deposits such as subretinal drusenoid deposits (SDD), increased lipid droplets in the RPE, basal lamellar deposits (BlamD) and membranous debris in the Bruch’s membrane. In addition, pigmentary abnormalities such as RPE hypertrophy, multilayered-RPE cells, and ectopic pigment granules outside the RPE were observed inCldn1cKO mice. Our study provides new insights into the possible association of the TJ protein claudin-1 with lipid metabolism and cellular ageing in the RPE contributing to the early onset of AMD.

show abstract

Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration

Cited by 25 publications

References 83 publications

Astaxanthin Ameliorates Diabetic Retinopathy in Swiss Albino Mice via Inhibitory Processes of Neuron-Specific Enolase Activity

Astaxanthin Ameliorates Diabetic Retinopathy in Swiss Albino Mice via Inhibitory Processes of Neuron-Specific Enolase Activity

Retinal Pigment Epithelium-Specific Ablation of GPx4 in Adult Mice Recapitulates Key Features of Geographic Atrophy in Age-Related Macular Degeneration

Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice

Contact Info

Product

Resources

About