TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation

Autores
Sachdeva, Robin; Schlotterer, Andrea; Schumacher, Dagmar; Matka, Christin; Mathar, Ilka; Dietrich, Nadine; Medert, Rebekka; Kriebs, Ulrich; Lin, Jihong; Nawroth, Peter; Birnbaumer, Lutz; Fleming, Thomas; Freichel, Marc; Hammes, Hans Peter
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Fil: Sachdeva, Robin. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Schlotterer, Andrea. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Schumacher, Dagmar. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Matka, Christin. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Mathar, Ilka. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Dietrich, Nadine. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Medert, Rebekka. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Kriebs, Ulrich. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Lin, Jihong. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Nawroth, Peter. University Hospital Heidelberg. Department of Medicine I and Clinical Chemistry; Alemania
Fil: Nawroth, Peter. German Center for Diabetes Research; Alemania
Fil: Nawroth, Peter. Institute for Diabetes and Cancer IDC Helmholtz Center Munich; Alemania
Fil: Nawroth, Peter. eidelberg University Hospital. Departament of Medicine I. Joint Heidelberg Institute for Diabetes and Cancer Translational Diabetes Program; Alemania
Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratoy; Estados Unidos
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Hammes, Hans-Peter. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Freichel, Marc. Heidelberg Universit. Institute of Pharmacology; Alemania
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.
Fuente
Molecular Metabolism. 2018;9:156-167
Materia
RETINOPATIA DIABETICA
ENFERMEDADES METABOLICAS
HIPERGLUCEMIA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
Repositorio Institucional (UCA)
Institución
Pontificia Universidad Católica Argentina
OAI Identificador
oai:ucacris:123456789/8705

id RIUCA_04d76a0e13af5dd2971f3a0ae3ba479f
oai_identifier_str oai:ucacris:123456789/8705
network_acronym_str RIUCA
repository_id_str 2585
network_name_str Repositorio Institucional (UCA)
spelling TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulationSachdeva, RobinSchlotterer, AndreaSchumacher, DagmarMatka, ChristinMathar, IlkaDietrich, NadineMedert, RebekkaKriebs, UlrichLin, JihongNawroth, PeterBirnbaumer, LutzFleming, ThomasFreichel, MarcHammes, Hans PeterRETINOPATIA DIABETICAENFERMEDADES METABOLICASHIPERGLUCEMIAFil: Sachdeva, Robin. Heidelberg Universit. Institute of Pharmacology; AlemaniaFil: Schlotterer, Andrea. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; AlemaniaFil: Schumacher, Dagmar. Heidelberg Universit. Institute of Pharmacology; AlemaniaFil: Matka, Christin. Heidelberg Universit. Institute of Pharmacology; AlemaniaFil: Mathar, Ilka. Heidelberg Universit. Institute of Pharmacology; AlemaniaFil: Dietrich, Nadine. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; AlemaniaFil: Medert, Rebekka. Heidelberg Universit. Institute of Pharmacology; AlemaniaFil: Kriebs, Ulrich. Heidelberg Universit. Institute of Pharmacology; AlemaniaFil: Lin, Jihong. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; AlemaniaFil: Nawroth, Peter. University Hospital Heidelberg. Department of Medicine I and Clinical Chemistry; AlemaniaFil: Nawroth, Peter. German Center for Diabetes Research; AlemaniaFil: Nawroth, Peter. Institute for Diabetes and Cancer IDC Helmholtz Center Munich; AlemaniaFil: Nawroth, Peter. eidelberg University Hospital. Departament of Medicine I. Joint Heidelberg Institute for Diabetes and Cancer Translational Diabetes Program; AlemaniaFil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratoy; Estados UnidosFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Hammes, Hans-Peter. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; AlemaniaFil: Freichel, Marc. Heidelberg Universit. Institute of Pharmacology; AlemaniaObjective 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.Elsevier2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://repositorio.uca.edu.ar/handle/123456789/87052212-877810.1016/j.molmet.2018.01.00329373286Sachdeva R, Schlotterer A, Schumacher D, et al. TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation [en línea]. Molecular Metabolism. 2018;9:156-167. doi:10.1016/j.molmet.2018.01.003 Disponible en:Molecular Metabolism. 2018;9:156-167reponame:Repositorio Institucional (UCA)instname:Pontificia Universidad Católica Argentinaenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/4.0/2025-07-03T10:56:54Zoai:ucacris:123456789/8705instacron:UCAInstitucionalhttps://repositorio.uca.edu.ar/Universidad privadaNo correspondehttps://repositorio.uca.edu.ar/oaiclaudia_fernandez@uca.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:25852025-07-03 10:56:55.055Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentinafalse
dc.title.none.fl_str_mv TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
title TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
spellingShingle TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
Sachdeva, Robin
RETINOPATIA DIABETICA
ENFERMEDADES METABOLICAS
HIPERGLUCEMIA
title_short TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
title_full TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
title_fullStr TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
title_full_unstemmed TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
title_sort TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation
dc.creator.none.fl_str_mv Sachdeva, Robin
Schlotterer, Andrea
Schumacher, Dagmar
Matka, Christin
Mathar, Ilka
Dietrich, Nadine
Medert, Rebekka
Kriebs, Ulrich
Lin, Jihong
Nawroth, Peter
Birnbaumer, Lutz
Fleming, Thomas
Freichel, Marc
Hammes, Hans Peter
author Sachdeva, Robin
author_facet Sachdeva, Robin
Schlotterer, Andrea
Schumacher, Dagmar
Matka, Christin
Mathar, Ilka
Dietrich, Nadine
Medert, Rebekka
Kriebs, Ulrich
Lin, Jihong
Nawroth, Peter
Birnbaumer, Lutz
Fleming, Thomas
Freichel, Marc
Hammes, Hans Peter
author_role author
author2 Schlotterer, Andrea
Schumacher, Dagmar
Matka, Christin
Mathar, Ilka
Dietrich, Nadine
Medert, Rebekka
Kriebs, Ulrich
Lin, Jihong
Nawroth, Peter
Birnbaumer, Lutz
Fleming, Thomas
Freichel, Marc
Hammes, Hans Peter
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv RETINOPATIA DIABETICA
ENFERMEDADES METABOLICAS
HIPERGLUCEMIA
topic RETINOPATIA DIABETICA
ENFERMEDADES METABOLICAS
HIPERGLUCEMIA
dc.description.none.fl_txt_mv Fil: Sachdeva, Robin. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Schlotterer, Andrea. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Schumacher, Dagmar. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Matka, Christin. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Mathar, Ilka. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Dietrich, Nadine. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Medert, Rebekka. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Kriebs, Ulrich. Heidelberg Universit. Institute of Pharmacology; Alemania
Fil: Lin, Jihong. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Nawroth, Peter. University Hospital Heidelberg. Department of Medicine I and Clinical Chemistry; Alemania
Fil: Nawroth, Peter. German Center for Diabetes Research; Alemania
Fil: Nawroth, Peter. Institute for Diabetes and Cancer IDC Helmholtz Center Munich; Alemania
Fil: Nawroth, Peter. eidelberg University Hospital. Departament of Medicine I. Joint Heidelberg Institute for Diabetes and Cancer Translational Diabetes Program; Alemania
Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratoy; Estados Unidos
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Hammes, Hans-Peter. Heidelberg Universit. Medical Faculty Mannheim. Vth Department of Medicine; Alemania
Fil: Freichel, Marc. Heidelberg Universit. Institute of Pharmacology; Alemania
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.
description Fil: Sachdeva, Robin. Heidelberg Universit. Institute of Pharmacology; Alemania
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://repositorio.uca.edu.ar/handle/123456789/8705
2212-8778
10.1016/j.molmet.2018.01.003
29373286
Sachdeva R, Schlotterer A, Schumacher D, et al. TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation [en línea]. Molecular Metabolism. 2018;9:156-167. doi:10.1016/j.molmet.2018.01.003 Disponible en:
url https://repositorio.uca.edu.ar/handle/123456789/8705
identifier_str_mv 2212-8778
10.1016/j.molmet.2018.01.003
29373286
Sachdeva R, Schlotterer A, Schumacher D, et al. TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation [en línea]. Molecular Metabolism. 2018;9:156-167. doi:10.1016/j.molmet.2018.01.003 Disponible en:
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Molecular Metabolism. 2018;9:156-167
reponame:Repositorio Institucional (UCA)
instname:Pontificia Universidad Católica Argentina
reponame_str Repositorio Institucional (UCA)
collection Repositorio Institucional (UCA)
instname_str Pontificia Universidad Católica Argentina
repository.name.fl_str_mv Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentina
repository.mail.fl_str_mv claudia_fernandez@uca.edu.ar
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