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dc.contributor.author
Sachdeva, Robin
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Schlotterer, Andrea
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Schumacher, Dagmar
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Matka, Christin
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Mathar, Ilka
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Dietrich, Nadine
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Medert, Rebekka
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Kriebs, Ulrich
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Lin, Jihong
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Nawroth, Peter
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Birnbaumer, Lutz
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Fleming, Thomas
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Hammes, Hans Peter
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Freichel, Marc
dc.date.available
2020-04-01T16:46:55Z
dc.date.issued
2018-03
dc.identifier.citation
Sachdeva, Robin; Schlotterer, Andrea; Schumacher, Dagmar; Matka, Christin; Mathar, Ilka; et al.; TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation; Elsevier; Molecular Metabolism; 9; 3-2018; 156-167
dc.identifier.issn
2212-8778
dc.identifier.uri
http://hdl.handle.net/11336/101534
dc.description.abstract
Objective: Diabetic retinopathy (DR) is induced by an accumulation of reactive metabolites such as ROS, RNS, and RCS species, which were reported to modulate the activity of cation channels of the TRPC family. In this study, we use Trpc1/4/5/6 / compound knockout mice to analyze the contribution of these TRPC proteins to diabetic retinopathy. Methods: We used Nanostring- and qPCR-based analysis to determine mRNA levels of TRPC channels in control and diabetic retinae and retinal cell types. Chronic hyperglycemia was induced by Streptozotocin (STZ) treatment. To assess the development of diabetic retinopathy, vasoregression, pericyte loss, and thickness of individual retinal layers were analyzed. Plasma and cellular methylglyoxal (MG) levels, as well as Glyoxalase 1 (GLO1) enzyme activity and protein expression, were measured in WT and Trpc1/4/5/6 / cells or tissues. MG-evoked toxicity in cells of both genotypes was compared by MTT assay. Results: We find that Trpc1/4/5/6 / mice are protected from hyperglycemia-evoked vasoregression determined by the formation of acellular capillaries and pericyte drop-out. In addition, Trpc1/4/5/6 / mice are resistant to the STZ-induced reduction in retinal layer thickness. The RCS metabolite methylglyoxal, which represents a key mediator for the development of diabetic retinopathy, was significantly reduced in plasma and red blood cells (RBCs) of STZ-treated Trpc1/4/5/6 / mice compared to controls. GLO1 is the major MG detoxifying enzyme, and its activity and protein expression were significantly elevated in Trpc1/4/5/6-deficient cells, which led to significantly increased resistance to MG toxicity. GLO1 activity was also increased in retinal extracts from Trpc1/4/5/6 / mice. The TRPCs investigated here are expressed at different levels in endothelial and glial cells of the retina. Conclusion: The protective phenotype in diabetic retinopathy observed in Trpc1/4/5/6 / mice is suggestive of a predominant action of TRPCs in Müller cells and microglia because of their central position in the retention of a proper homoeostasis of the neurovascular unit.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
MethylGlyoxal
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TRPC cation channels
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Reactive metabolites
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Diabetic retinopathy
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Vasoregression; Glyoxalase
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Biología Celular, Microbiología
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-03-10T12:28:33Z
dc.journal.volume
9
dc.journal.pagination
156-167
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Sachdeva, Robin. Heidelberg University; Alemania
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Fil: Schlotterer, Andrea. Heidelberg University; Alemania
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Fil: Schumacher, Dagmar. Heidelberg University; Alemania
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Fil: Matka, Christin. Heidelberg University; Alemania
dc.description.fil
Fil: Mathar, Ilka. Heidelberg University; Alemania
dc.description.fil
Fil: Dietrich, Nadine. Heidelberg University; Alemania
dc.description.fil
Fil: Medert, Rebekka. Heidelberg University; Alemania
dc.description.fil
Fil: Kriebs, Ulrich. Heidelberg University; Alemania
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Fil: Lin, Jihong. Heidelberg University; Alemania
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Fil: Nawroth, Peter. Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Neuherberg; Alemania. University Hospital Heidelberg; Alemania. German Center for Diabetes Research; Alemania
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Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences; Estados Unidos. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
dc.description.fil
Fil: Fleming, Thomas. University Hospital Heidelberg; Alemania. German Center for Diabetes Research; Alemania
dc.description.fil
Fil: Hammes, Hans Peter. Heidelberg University; Alemania
dc.description.fil
Fil: Freichel, Marc. Heidelberg University; Alemania
dc.journal.title
Molecular Metabolism
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://linkinghub.elsevier.com/retrieve/pii/S2212877817306282
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.molmet.2018.01.003
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