Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

Potilinski, María Constanza; Lorenc, Valeria E.; Perisset, Sofía; Gallo, Juan E.

doi:10.3390/ijms21072351

Cited by 34 publications

(21 citation statements)

References 172 publications

(191 reference statements)

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“… 46 Diabetes also induces changes in blood vessels and chronic inflammation in the retina and eventually caused retinal ganglion cell loss. 47 Our data showed apparently increased inflammatory cells infiltration and significant elevated inflammatory cytokines expression in the MG of DM rats. ERK1/2 NF-κB plays an important role in regulating inflammatory responses.…”

Section: Discussionsupporting

confidence: 53%

Hyperglycemia Induces Meibomian Gland Dysfunction

Guo

Zhang

Zhao

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the pathological change of MG induced by diabetes in a rat model. Methods Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic animal model. Lipid accumulation in MG was detected by Oil Red O staining and LipidTox staining. Cell proliferation status was determined by Ki67 and P63 immunostaining, whereas cell apoptosis was confirmed by TUNEL assay. Gene expression of inflammatory cytokines and adhesion molecules IL-1α, IL-1β, ELAM1, ICAM1, and VCAM1 were detected by RT-PCR. Activation of ERK, NF-κB, and AMPK signaling pathways was determined by Western Blot analysis. Oxidative stress-related factors NOX4, 4HNE, Nrf2, HO-1, and SOD2 were detected by immunostaining or Western Blot analysis. Tom20 and Tim23 immunostaining and transmission electron microscopy were performed to evaluate the mitochondria functional and structure change. Results Four months after STZ injection, there was acini dropout in MG of diabetic rats. Evident infiltration of inflammatory cells, increased expression of inflammatory factors, and adhesion molecules, as well as activated ERK and NF-κB signaling pathways were identified. Oxidative stress of MG was evident in 4-month diabetic rats. Phospho-AMPK was downregulated in MG of 2-month diabetic rats and more prominent in 4-month rats. After metformin treatment, phospho-AMPK was upregulated and the morphology of MG was well maintained. Moreover, inflammation and oxidative stress of MG were alleviated after metformin intervention. Conclusions Long-term diabetes may lead to Meibomian gland dysfunction (MGD). AMPK may be a therapeutic target of MGD induced by diabetes.

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Section: Discussionsupporting

confidence: 53%

Hyperglycemia Induces Meibomian Gland Dysfunction

Guo

Zhang

Zhao

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…Post-translational modifications in general, and phosphorylation in particular, are key mechanisms of regulation of protein function, a phenomenon well-characterized for αB-crystallins. Phosphorylation of HspB5/αB-crystallin can be induced by MAPKs including extracellular-signal-regulated kinase (ERK) and p38 under stress conditions [ 48 , 49 ], which eventually regulates its intracellular distribution, translocation, and chaperone activity [ 50 , 51 ] and also enhances its anti-apoptotic potential [ 52 ]. Although, earlier in vivo studies had shown HspB4/αA-crystallin in the lens can be phosphorylated at residue-122 and 148, unlike HspB5/αB-crystallin, detailed functional studies for HspB4/αA-crystallin phosphorylation are very limited [ 53 , 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

HspB4/αA-Crystallin Modulates Neuroinflammation in the Retina via the Stress-Specific Inflammatory Pathways

Nath

Shan

Myers

et al. 2021

JCM

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Purpose: We have previously demonstrated that HspB4/αA-crystallin, a molecular chaperone, plays an important intrinsic neuroprotective role during diabetes, by its phosphorylation on residue 148. We also reported that HspB4/αA-crystallin is highly expressed by glial cells. There is a growing interest in the potential causative role of low-grade inflammation in diabetic retinopathy pathophysiology and retinal Müller glial cells’ (MGCs’) participation in the inflammatory response. MGCs indeed play a central role in retinal homeostasis via secreting various cytokines and other mediators. Hence, this study was carried out to delineate and understand the regulatory function of HspB4/αA-crystallin in the inflammatory response associated with metabolic stresses. Methods: Primary MGCs were isolated from knockout HspB4/αA-crystallin mice. These primary cells were then transfected with plasmids encoding either wild-type (WT), phosphomimetic (T148D), or non-phosphorylatable mutants (T148A) of HspB4/αA-crystallin. The cells were exposed to multiple metabolic stresses including serum starvation (SS) or high glucose with TNF-alpha (HG + T) before being further evaluated for the expression of inflammatory markers by qPCR. The total protein expression along with subcellular localization of NF-kB and the NLRP3 component was assessed by Western blot. Results: Elevated levels of IL-6, IL-1β, MCP-1, and IL-18 in SS were significantly diminished in MGCs overexpressing WT and further in T148D as compared to EV. The HG + T-induced increase in these inflammatory markers was also dampened by WT and even more significantly by T148D overexpression, whereas T148A was ineffective in either stress. Further analysis revealed that overexpression of WT or the T148D, also led to a significant reduction of Nlrp3, Asc, and caspase-1 transcript expression in serum-deprived MGCs and nearly abolished the NF-kB induction in HG + T diabetes-like stress. This mechanistic effect was further evaluated at the protein level and confirmed the stress-dependent regulation of NLRP3 and NF-kB by αA-crystallin. Conclusions: The data gathered in this study demonstrate the central regulatory role of HspB4/αA-crystallin and its modulation by phosphorylation on T148 in retinal MGCs. For the first time, this study demonstrates that HspB4/αA-crystallin can dampen the stress-induced expression of pro-inflammatory cytokines through the modulation of multiple key inflammatory pathways, therefore, suggesting its potential as a therapeutic target for the modulation of chronic neuroinflammation.

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“…Post-translational modi cations in general, and phosphorylation in particular, are key mechanisms of regulation of protein function, a phenomenon well-characterized for aB-crystallins. Phosphorylation of αB-crystallin can be induced by MAPKs including extracellular signal-regulated kinase (ERK) and p38 under stress conditions (46,47), which eventually regulates its intracellular distribution, translocation, chaperone activity (48,49) and also enhances its anti-apoptotic potential (50). Although, earlier in-vivo studies had shown αA-crystallin in the lens can be phosphorylated at residue-122 and 148, unlike αBcrystallin, detailed functional studies for αA-crystallin phosphorylation are very limited (51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

αA-Crystallin modulates neuroinflammation in the retina via stress-specific inflammatory pathways

Nath

Shan

Myers

et al. 2021

Preprint

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Purpose We have previously demonstrated that αA-crystallin, a molecular chaperone, plays an important intrinsic neuroprotective role during diabetes, by its phosphorylation on residue 148. We also reported that αA-crystallin is highly expressed by glial cells. There is a growing interest in the potential causative role of low-grade inflammation in diabetic retinopathy pathophysiology and retinal Müller glial cells (MGCs) participation in the inflammatory response. MGCs indeed play a central role in retinal homeostasis via secreting various cytokines and other mediators. Hence, this study was carried out to delineate and understand the regulatory function of αA-crystallin in the inflammatory response associated with metabolic stresses. Methods Primary MGCs were isolated from Ko-αA-crystallin mice. These primary cells were then transfected with plasmids encoding either wild-type (WT), phosphomimetic (T148D), or non-phosphorylatable mutants (T148A) of αA-crystallin. The cells were exposed to multiple metabolic stress including serum starvation (SS) or high glucose with TNF-alpha (HG + T) before being further evaluated for the expression of inflammatory markers by qPCR. The total protein expression along with subcellular localization of NF-kB & NLRP3 component was assessed by western blot. Results Elevated levels of IL-6, IL-1β, MCP-1, and IL-18 in SS were significantly diminished in MGCs overexpressing WT and further in T148D as compared to EV. The HG + T-induced increase in these inflammatory markers was also dampened by WT and even more significantly by T148D overexpression, whereas T148A was ineffective in either stress. Further analysis revealed that overexpression of WT or the T148D, also lead to a significant reduction of Nlrp3, Asc, and caspase-1 transcript expression in serum-deprived MGCs and nearly abolished the NF-kB induction in HG + T diabetes-like stress. This mechanistic effect was further evaluated at the protein level and confirmed the stress-dependent regulation of NLRP3 and NF-kB by αA-crystallin. Conclusion The data gathered in this study demonstrate the central regulatory role of αA-crystallin and its modulation by phosphorylation on T148 in retinal MGCs. For the first time, this study demonstrates that αA-crystallin can dampen the stress-induced expression of pro-inflammatory cytokines through modulation of multiple key inflammatory pathways, therefore, suggesting its potential as a therapeutic target for modulation of chronic neuroinflammation.

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Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

Cited by 34 publications

References 172 publications

Hyperglycemia Induces Meibomian Gland Dysfunction

Hyperglycemia Induces Meibomian Gland Dysfunction

HspB4/αA-Crystallin Modulates Neuroinflammation in the Retina via the Stress-Specific Inflammatory Pathways

αA-Crystallin modulates neuroinflammation in the retina via stress-specific inflammatory pathways

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