Defective Autophagy in Diabetic Retinopathy
Müller cells (MCs) are a major source of VEGF in diabetic retinopathy (DR). Vascular endothelial growth factor is the main therapeutic target for treating DR. This study aimed to investigate whether autophagy is involved in MC response under high glucose (HG). Rat retinal Müller cells (rMCs) were ex...
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| Veröffentlicht in: | Investigative ophthalmology & visual science 2016-08, Vol.57 (10), p.4356-4366 |
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| creator | Lopes de Faria, Jacqueline M Duarte, Diego A Montemurro, Chiara Papadimitriou, Alexandros Consonni, Sílvio Roberto Lopes de Faria, José B |
| description | Müller cells (MCs) are a major source of VEGF in diabetic retinopathy (DR). Vascular endothelial growth factor is the main therapeutic target for treating DR. This study aimed to investigate whether autophagy is involved in MC response under high glucose (HG).
Rat retinal Müller cells (rMCs) were exposed to normal or high glucose in and out of presence of pharmacologic inhibitors and activators and small interfering RNA (siRNA) for p62/SQTSM1 for 24 hours.
High glucose induces increase of early and late autophagic markers, accumulation of p62/SQTSM1 and endoplasmic reticulum (ER) stress response associated with apoptosis augmentation (P < 0.01). The inhibition of autophagy in HG leads to higher rMC apoptotic rate (P < 0.001). By silencing the p62/SQTSM1, ER stress is ameliorated (p |
| doi_str_mv | 10.1167/iovs.16-19197 |
| format | Article |
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Rat retinal Müller cells (rMCs) were exposed to normal or high glucose in and out of presence of pharmacologic inhibitors and activators and small interfering RNA (siRNA) for p62/SQTSM1 for 24 hours.
High glucose induces increase of early and late autophagic markers, accumulation of p62/SQTSM1 and endoplasmic reticulum (ER) stress response associated with apoptosis augmentation (P < 0.01). The inhibition of autophagy in HG leads to higher rMC apoptotic rate (P < 0.001). By silencing the p62/SQTSM1, ER stress is ameliorated (p<0.0001), preventing apoptosis. Retinal MCs in HG treated with rapamycin (mTOR inhibitor) show autophagy machinery activation and reestablishment of cargo degradation, protecting cells from apoptosis (P < 0.0001). Rapamycin improves lysosomal proteolytic activity by improving cathepsin L activity restoring autophagic cargo degradation, and preventing increased VEGF release (P < 0.0001). In experimental model of diabetes, Beclin-1 and p62/SQTSM-1 were found to be marked increased in retinas from diabetic Wystar Kyoto rats compared with control group (P < 0.003) with reduction of cathepsin L activity.
High glucose upregulates autophagy but accumulates p62/SQTSM1 cargo due to lysosomal dysfunction, leading to massive VEGF release and cell death of rMCs. Lysosomal impairment and autophagic dysfunction are early events present in the pathogenesis of diabetic retinopathy (DR). This might be valuable for developing a novel therapeutic strategy to treat DR.]]></description><identifier>ISSN: 1552-5783</identifier><identifier>EISSN: 1552-5783</identifier><identifier>DOI: 10.1167/iovs.16-19197</identifier><identifier>PMID: 27564518</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis ; Autophagy - drug effects ; Autophagy - physiology ; Blotting, Western ; Cells, Cultured ; Diabetes Mellitus, Experimental ; Diabetic Retinopathy - genetics ; Diabetic Retinopathy - metabolism ; Diabetic Retinopathy - pathology ; Ependymoglial Cells - metabolism ; Ependymoglial Cells - ultrastructure ; Gene Expression Regulation ; Glucose - pharmacology ; Microscopy, Electron, Transmission ; Oxidative Stress ; Rats ; Retina - metabolism ; Retina - pathology ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Sequestosome-1 Protein - biosynthesis ; Sequestosome-1 Protein - genetics ; Sweetening Agents - pharmacology</subject><ispartof>Investigative ophthalmology & visual science, 2016-08, Vol.57 (10), p.4356-4366</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-dd2d65b52f33b6e44369ad425b5efdb2d040a9d6aa529e0e5192138e962cd3973</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27564518$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lopes de Faria, Jacqueline M</creatorcontrib><creatorcontrib>Duarte, Diego A</creatorcontrib><creatorcontrib>Montemurro, Chiara</creatorcontrib><creatorcontrib>Papadimitriou, Alexandros</creatorcontrib><creatorcontrib>Consonni, Sílvio Roberto</creatorcontrib><creatorcontrib>Lopes de Faria, José B</creatorcontrib><title>Defective Autophagy in Diabetic Retinopathy</title><title>Investigative ophthalmology & visual science</title><addtitle>Invest Ophthalmol Vis Sci</addtitle><description><![CDATA[Müller cells (MCs) are a major source of VEGF in diabetic retinopathy (DR). Vascular endothelial growth factor is the main therapeutic target for treating DR. This study aimed to investigate whether autophagy is involved in MC response under high glucose (HG).
Rat retinal Müller cells (rMCs) were exposed to normal or high glucose in and out of presence of pharmacologic inhibitors and activators and small interfering RNA (siRNA) for p62/SQTSM1 for 24 hours.
High glucose induces increase of early and late autophagic markers, accumulation of p62/SQTSM1 and endoplasmic reticulum (ER) stress response associated with apoptosis augmentation (P < 0.01). The inhibition of autophagy in HG leads to higher rMC apoptotic rate (P < 0.001). By silencing the p62/SQTSM1, ER stress is ameliorated (p<0.0001), preventing apoptosis. Retinal MCs in HG treated with rapamycin (mTOR inhibitor) show autophagy machinery activation and reestablishment of cargo degradation, protecting cells from apoptosis (P < 0.0001). Rapamycin improves lysosomal proteolytic activity by improving cathepsin L activity restoring autophagic cargo degradation, and preventing increased VEGF release (P < 0.0001). In experimental model of diabetes, Beclin-1 and p62/SQTSM-1 were found to be marked increased in retinas from diabetic Wystar Kyoto rats compared with control group (P < 0.003) with reduction of cathepsin L activity.
High glucose upregulates autophagy but accumulates p62/SQTSM1 cargo due to lysosomal dysfunction, leading to massive VEGF release and cell death of rMCs. Lysosomal impairment and autophagic dysfunction are early events present in the pathogenesis of diabetic retinopathy (DR). This might be valuable for developing a novel therapeutic strategy to treat DR.]]></description><subject>Animals</subject><subject>Apoptosis</subject><subject>Autophagy - drug effects</subject><subject>Autophagy - physiology</subject><subject>Blotting, Western</subject><subject>Cells, Cultured</subject><subject>Diabetes Mellitus, Experimental</subject><subject>Diabetic Retinopathy - genetics</subject><subject>Diabetic Retinopathy - metabolism</subject><subject>Diabetic Retinopathy - pathology</subject><subject>Ependymoglial Cells - metabolism</subject><subject>Ependymoglial Cells - ultrastructure</subject><subject>Gene Expression Regulation</subject><subject>Glucose - pharmacology</subject><subject>Microscopy, Electron, Transmission</subject><subject>Oxidative Stress</subject><subject>Rats</subject><subject>Retina - metabolism</subject><subject>Retina - pathology</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Sequestosome-1 Protein - biosynthesis</subject><subject>Sequestosome-1 Protein - genetics</subject><subject>Sweetening Agents - pharmacology</subject><issn>1552-5783</issn><issn>1552-5783</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEtLw0AUhQdRbK0u3UqWgqTOnclMMsvS1gcUBNH1MMnc2JG8zCSF_HtTW8XNuYfLx1l8hFwDnQPI-N7VOz8HGYICFZ-QKQjBQhEn_PRfn5AL7z8pZQCMnpMJi4WMBCRTcrfCHLPO7TBY9F3dbM3HELgqWDmTYuey4HXMqm5Mtx0uyVluCo9Xxzsj7w_rt-VTuHl5fF4uNmHGVdKF1jIrRSpYznkqMYq4VMZGbHxhblNmaUSNstIYwRRSFKAY8ASVZJnlKuYzcnvYbdr6q0ff6dL5DIvCVFj3XkMCgkueMDGi4QHN2tr7FnPdtK407aCB6r0fvfejQeofPyN_c5zu0xLtH_0rhH8D7vlgJQ</recordid><startdate>20160801</startdate><enddate>20160801</enddate><creator>Lopes de Faria, Jacqueline M</creator><creator>Duarte, Diego A</creator><creator>Montemurro, Chiara</creator><creator>Papadimitriou, Alexandros</creator><creator>Consonni, Sílvio Roberto</creator><creator>Lopes de Faria, José B</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20160801</creationdate><title>Defective Autophagy in Diabetic Retinopathy</title><author>Lopes de Faria, Jacqueline M ; Duarte, Diego A ; Montemurro, Chiara ; Papadimitriou, Alexandros ; Consonni, Sílvio Roberto ; Lopes de Faria, José B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-dd2d65b52f33b6e44369ad425b5efdb2d040a9d6aa529e0e5192138e962cd3973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Autophagy - drug effects</topic><topic>Autophagy - physiology</topic><topic>Blotting, Western</topic><topic>Cells, Cultured</topic><topic>Diabetes Mellitus, Experimental</topic><topic>Diabetic Retinopathy - genetics</topic><topic>Diabetic Retinopathy - metabolism</topic><topic>Diabetic Retinopathy - pathology</topic><topic>Ependymoglial Cells - metabolism</topic><topic>Ependymoglial Cells - ultrastructure</topic><topic>Gene Expression Regulation</topic><topic>Glucose - pharmacology</topic><topic>Microscopy, Electron, Transmission</topic><topic>Oxidative Stress</topic><topic>Rats</topic><topic>Retina - metabolism</topic><topic>Retina - pathology</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Sequestosome-1 Protein - biosynthesis</topic><topic>Sequestosome-1 Protein - genetics</topic><topic>Sweetening Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lopes de Faria, Jacqueline M</creatorcontrib><creatorcontrib>Duarte, Diego A</creatorcontrib><creatorcontrib>Montemurro, Chiara</creatorcontrib><creatorcontrib>Papadimitriou, Alexandros</creatorcontrib><creatorcontrib>Consonni, Sílvio Roberto</creatorcontrib><creatorcontrib>Lopes de Faria, José B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Investigative ophthalmology & visual science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lopes de Faria, Jacqueline M</au><au>Duarte, Diego A</au><au>Montemurro, Chiara</au><au>Papadimitriou, Alexandros</au><au>Consonni, Sílvio Roberto</au><au>Lopes de Faria, José B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defective Autophagy in Diabetic Retinopathy</atitle><jtitle>Investigative ophthalmology & visual science</jtitle><addtitle>Invest Ophthalmol Vis Sci</addtitle><date>2016-08-01</date><risdate>2016</risdate><volume>57</volume><issue>10</issue><spage>4356</spage><epage>4366</epage><pages>4356-4366</pages><issn>1552-5783</issn><eissn>1552-5783</eissn><abstract><![CDATA[Müller cells (MCs) are a major source of VEGF in diabetic retinopathy (DR). Vascular endothelial growth factor is the main therapeutic target for treating DR. This study aimed to investigate whether autophagy is involved in MC response under high glucose (HG).
Rat retinal Müller cells (rMCs) were exposed to normal or high glucose in and out of presence of pharmacologic inhibitors and activators and small interfering RNA (siRNA) for p62/SQTSM1 for 24 hours.
High glucose induces increase of early and late autophagic markers, accumulation of p62/SQTSM1 and endoplasmic reticulum (ER) stress response associated with apoptosis augmentation (P < 0.01). The inhibition of autophagy in HG leads to higher rMC apoptotic rate (P < 0.001). By silencing the p62/SQTSM1, ER stress is ameliorated (p<0.0001), preventing apoptosis. Retinal MCs in HG treated with rapamycin (mTOR inhibitor) show autophagy machinery activation and reestablishment of cargo degradation, protecting cells from apoptosis (P < 0.0001). Rapamycin improves lysosomal proteolytic activity by improving cathepsin L activity restoring autophagic cargo degradation, and preventing increased VEGF release (P < 0.0001). In experimental model of diabetes, Beclin-1 and p62/SQTSM-1 were found to be marked increased in retinas from diabetic Wystar Kyoto rats compared with control group (P < 0.003) with reduction of cathepsin L activity.
High glucose upregulates autophagy but accumulates p62/SQTSM1 cargo due to lysosomal dysfunction, leading to massive VEGF release and cell death of rMCs. Lysosomal impairment and autophagic dysfunction are early events present in the pathogenesis of diabetic retinopathy (DR). This might be valuable for developing a novel therapeutic strategy to treat DR.]]></abstract><cop>United States</cop><pmid>27564518</pmid><doi>10.1167/iovs.16-19197</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Apoptosis Autophagy - drug effects Autophagy - physiology Blotting, Western Cells, Cultured Diabetes Mellitus, Experimental Diabetic Retinopathy - genetics Diabetic Retinopathy - metabolism Diabetic Retinopathy - pathology Ependymoglial Cells - metabolism Ependymoglial Cells - ultrastructure Gene Expression Regulation Glucose - pharmacology Microscopy, Electron, Transmission Oxidative Stress Rats Retina - metabolism Retina - pathology RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Sequestosome-1 Protein - biosynthesis Sequestosome-1 Protein - genetics Sweetening Agents - pharmacology |
| title | Defective Autophagy in Diabetic Retinopathy |
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