Loading…
Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model
To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model. Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal inject...
Saved in:
| Published in: | Investigative ophthalmology & visual science 2021-10, Vol.62 (13), p.18-18 |
|---|---|
| Main Authors: | , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13 |
| container_end_page | 18 |
| container_issue | 13 |
| container_start_page | 18 |
| container_title | Investigative ophthalmology & visual science |
| container_volume | 62 |
| creator | Van Bergen, Tine Hu, Tjing-Tjing Little, Karis De Groef, Lies Moons, Lieve Stitt, Alan W Vermassen, Elke Feyen, Jean H M |
| description | To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model.
Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness.
Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels.
These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME. |
| doi_str_mv | 10.1167/iovs.62.13.18 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8556562</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2584437994</sourcerecordid><originalsourceid>FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13</originalsourceid><addsrcrecordid>eNpVkU1P3DAQhi3UqlDaI1fkIxyy9UfsOBekFtqC-ChaLerRmjiTXYM33trZlbj1pzcrKILTO9I8emakl5ADziac6-qLj5s80WLC5YSbHbLHlRKFqox892reJR9zvmdMcC7YB7IrS11VStd75O8M0hwH38_pbYC8BHoJIfiHhL6nv_2woEBv4gYD_ebdowve0VtcDb5FetEvfOOHmOjR7Hxa8LI-plNs1w7zmKMSAp0tvHvAfqsffUDPPDTjytEpDPQ6thg-kfcdhIyfn3Of3P34Pjs9L65-_bw4_XpVOGmqodDGOS0aXRvDoOw4Q47CINZCcyUlgmStaKRkCkAI7GTnjBKNq13VMmi53CcnT97Vulli67AfEgS7Sn4J6dFG8PbtpvcLO48ba5TSSotRcPQsSPHPGvNglz47DAF6jOtshTJlKau6Lke0eEJdijkn7F7OcGa3rdlta1YLy6XlZuQPX__2Qv-vSf4DlV2UpA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2584437994</pqid></control><display><type>article</type><title>Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model</title><source>PubMed Central（OA）</source><creator>Van Bergen, Tine ; Hu, Tjing-Tjing ; Little, Karis ; De Groef, Lies ; Moons, Lieve ; Stitt, Alan W ; Vermassen, Elke ; Feyen, Jean H M</creator><creatorcontrib>Van Bergen, Tine ; Hu, Tjing-Tjing ; Little, Karis ; De Groef, Lies ; Moons, Lieve ; Stitt, Alan W ; Vermassen, Elke ; Feyen, Jean H M</creatorcontrib><description>To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model.
Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness.
Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels.
These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME.</description><identifier>ISSN: 1552-5783</identifier><identifier>ISSN: 0146-0404</identifier><identifier>EISSN: 1552-5783</identifier><identifier>DOI: 10.1167/iovs.62.13.18</identifier><identifier>PMID: 34677569</identifier><language>eng</language><publisher>United States: The Association for Research in Vision and Ophthalmology</publisher><subject>Animals ; Anticoagulants - administration & dosage ; Biomarkers - blood ; Diabetes Mellitus, Experimental ; Diabetic Retinopathy - blood ; Diabetic Retinopathy - pathology ; Intravitreal Injections ; Male ; Plasma Kallikrein - antagonists & inhibitors ; Plasma Kallikrein - metabolism ; Rats ; Rats, Inbred BN ; Retina ; Retina - metabolism ; Retina - pathology ; Tomography, Optical Coherence - methods</subject><ispartof>Investigative ophthalmology & visual science, 2021-10, Vol.62 (13), p.18-18</ispartof><rights>Copyright 2021 The Authors 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13</citedby><cites>FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556562/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556562/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34677569$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Van Bergen, Tine</creatorcontrib><creatorcontrib>Hu, Tjing-Tjing</creatorcontrib><creatorcontrib>Little, Karis</creatorcontrib><creatorcontrib>De Groef, Lies</creatorcontrib><creatorcontrib>Moons, Lieve</creatorcontrib><creatorcontrib>Stitt, Alan W</creatorcontrib><creatorcontrib>Vermassen, Elke</creatorcontrib><creatorcontrib>Feyen, Jean H M</creatorcontrib><title>Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model</title><title>Investigative ophthalmology & visual science</title><addtitle>Invest Ophthalmol Vis Sci</addtitle><description>To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model.
Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness.
Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels.
These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME.</description><subject>Animals</subject><subject>Anticoagulants - administration & dosage</subject><subject>Biomarkers - blood</subject><subject>Diabetes Mellitus, Experimental</subject><subject>Diabetic Retinopathy - blood</subject><subject>Diabetic Retinopathy - pathology</subject><subject>Intravitreal Injections</subject><subject>Male</subject><subject>Plasma Kallikrein - antagonists & inhibitors</subject><subject>Plasma Kallikrein - metabolism</subject><subject>Rats</subject><subject>Rats, Inbred BN</subject><subject>Retina</subject><subject>Retina - metabolism</subject><subject>Retina - pathology</subject><subject>Tomography, Optical Coherence - methods</subject><issn>1552-5783</issn><issn>0146-0404</issn><issn>1552-5783</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpVkU1P3DAQhi3UqlDaI1fkIxyy9UfsOBekFtqC-ChaLerRmjiTXYM33trZlbj1pzcrKILTO9I8emakl5ADziac6-qLj5s80WLC5YSbHbLHlRKFqox892reJR9zvmdMcC7YB7IrS11VStd75O8M0hwH38_pbYC8BHoJIfiHhL6nv_2woEBv4gYD_ebdowve0VtcDb5FetEvfOOHmOjR7Hxa8LI-plNs1w7zmKMSAp0tvHvAfqsffUDPPDTjytEpDPQ6thg-kfcdhIyfn3Of3P34Pjs9L65-_bw4_XpVOGmqodDGOS0aXRvDoOw4Q47CINZCcyUlgmStaKRkCkAI7GTnjBKNq13VMmi53CcnT97Vulli67AfEgS7Sn4J6dFG8PbtpvcLO48ba5TSSotRcPQsSPHPGvNglz47DAF6jOtshTJlKau6Lke0eEJdijkn7F7OcGa3rdlta1YLy6XlZuQPX__2Qv-vSf4DlV2UpA</recordid><startdate>20211022</startdate><enddate>20211022</enddate><creator>Van Bergen, Tine</creator><creator>Hu, Tjing-Tjing</creator><creator>Little, Karis</creator><creator>De Groef, Lies</creator><creator>Moons, Lieve</creator><creator>Stitt, Alan W</creator><creator>Vermassen, Elke</creator><creator>Feyen, Jean H M</creator><general>The Association for Research in Vision and Ophthalmology</general><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><scope>5PM</scope></search><sort><creationdate>20211022</creationdate><title>Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model</title><author>Van Bergen, Tine ; Hu, Tjing-Tjing ; Little, Karis ; De Groef, Lies ; Moons, Lieve ; Stitt, Alan W ; Vermassen, Elke ; Feyen, Jean H M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Anticoagulants - administration & dosage</topic><topic>Biomarkers - blood</topic><topic>Diabetes Mellitus, Experimental</topic><topic>Diabetic Retinopathy - blood</topic><topic>Diabetic Retinopathy - pathology</topic><topic>Intravitreal Injections</topic><topic>Male</topic><topic>Plasma Kallikrein - antagonists & inhibitors</topic><topic>Plasma Kallikrein - metabolism</topic><topic>Rats</topic><topic>Rats, Inbred BN</topic><topic>Retina</topic><topic>Retina - metabolism</topic><topic>Retina - pathology</topic><topic>Tomography, Optical Coherence - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Van Bergen, Tine</creatorcontrib><creatorcontrib>Hu, Tjing-Tjing</creatorcontrib><creatorcontrib>Little, Karis</creatorcontrib><creatorcontrib>De Groef, Lies</creatorcontrib><creatorcontrib>Moons, Lieve</creatorcontrib><creatorcontrib>Stitt, Alan W</creatorcontrib><creatorcontrib>Vermassen, Elke</creatorcontrib><creatorcontrib>Feyen, Jean H M</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Investigative ophthalmology & visual science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Van Bergen, Tine</au><au>Hu, Tjing-Tjing</au><au>Little, Karis</au><au>De Groef, Lies</au><au>Moons, Lieve</au><au>Stitt, Alan W</au><au>Vermassen, Elke</au><au>Feyen, Jean H M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model</atitle><jtitle>Investigative ophthalmology & visual science</jtitle><addtitle>Invest Ophthalmol Vis Sci</addtitle><date>2021-10-22</date><risdate>2021</risdate><volume>62</volume><issue>13</issue><spage>18</spage><epage>18</epage><pages>18-18</pages><issn>1552-5783</issn><issn>0146-0404</issn><eissn>1552-5783</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model.
Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness.
Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels.
These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME.</abstract><cop>United States</cop><pub>The Association for Research in Vision and Ophthalmology</pub><pmid>34677569</pmid><doi>10.1167/iovs.62.13.18</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1552-5783 |
| ispartof | Investigative ophthalmology & visual science, 2021-10, Vol.62 (13), p.18-18 |
| issn | 1552-5783 0146-0404 1552-5783 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8556562 |
| source | PubMed Central（OA） |
| subjects | Animals Anticoagulants - administration & dosage Biomarkers - blood Diabetes Mellitus, Experimental Diabetic Retinopathy - blood Diabetic Retinopathy - pathology Intravitreal Injections Male Plasma Kallikrein - antagonists & inhibitors Plasma Kallikrein - metabolism Rats Rats, Inbred BN Retina Retina - metabolism Retina - pathology Tomography, Optical Coherence - methods |
| title | Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T02%3A01%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20Plasma%20Kallikrein%20With%20a%20Novel%20Bicyclic%20Peptide%20Inhibitor%20(THR-149)%20Reduces%20Retinal%20Thickening%20in%20a%20Diabetic%20Rat%20Model&rft.jtitle=Investigative%20ophthalmology%20&%20visual%20science&rft.au=Van%20Bergen,%20Tine&rft.date=2021-10-22&rft.volume=62&rft.issue=13&rft.spage=18&rft.epage=18&rft.pages=18-18&rft.issn=1552-5783&rft.eissn=1552-5783&rft_id=info:doi/10.1167/iovs.62.13.18&rft_dat=%3Cproquest_pubme%3E2584437994%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c387t-68cc62b69880a4f10e1e28ee9261533ea30d2b3305aa22ef3fc852bc9c7d0ad13%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2584437994&rft_id=info:pmid/34677569&rfr_iscdi=true |