Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma

Abstract Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO data...

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Autores principales:	Sujith Kumar Pulukool, Sai Krishna Srimadh Bhagavatham, Vishnu Kannan, Piruthivi Sukumar, Rajesh Babu Dandamudi, Shamika Ghaisas, Haripriya Kunchala, Darshan Saieesh, Ashwin Ashok Naik, Ashish Pargaonkar, Anuj Sharma, Venketesh Sivaramakrishnan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7c8d5e80c6984f2a9a441ababc5e7595
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spelling	oai:doaj.org-article:7c8d5e80c6984f2a9a441ababc5e75952021-12-02T14:42:52ZElevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma10.1038/s41598-021-89137-z2045-2322https://doaj.org/article/7c8d5e80c6984f2a9a441ababc5e75952021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89137-zhttps://doaj.org/toc/2045-2322Abstract Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO datasets to identify features unique to POAG. N9 microglial cells are used to gain mechanistic insights. Our POAG cohort showed elevated ATP in aqueous humor and cytokines in plasma. Metabolomic analysis showed changes in 21 metabolites including Dimethylarginine (DMAG) and activation of tryptophan metabolism in POAG. Analysis of GEO data sets and previously published proteomic data sets bins genes into signaling and metabolic pathways. Pathways from reanalyzed metabolomic data from literature significantly overlapped with those from our POAG data. DMAG modulated purinergic signaling, ATP secretion and cytokine expression were inhibited by N-Ethylmaleimide, NO donors, BAPTA and purinergic receptor inhibitors. ATP induced elevated intracellular calcium level and cytokines expression were inhibited by BAPTA. Metabolomics of cell culture supernatant from ATP treated sets showed metabolic deregulation and activation of tryptophan metabolism. DMAG and ATP induced IDO1/2 and TDO2 were inhibited by N-Ethylmaleimide, sodium nitroprusside and BAPTA. Our data obtained from clinical samples and cell culture studies reveal a strong association of elevated DMAG, ATP, cytokines and activation of tryptophan metabolism with POAG. DMAG mediated ATP signaling, inflammation and metabolic remodeling in microglia might have implications in management of POAG.Sujith Kumar PulukoolSai Krishna Srimadh BhagavathamVishnu KannanPiruthivi SukumarRajesh Babu DandamudiShamika GhaisasHaripriya KunchalaDarshan SaieeshAshwin Ashok NaikAshish PargaonkarAnuj SharmaVenketesh SivaramakrishnanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sujith Kumar Pulukool Sai Krishna Srimadh Bhagavatham Vishnu Kannan Piruthivi Sukumar Rajesh Babu Dandamudi Shamika Ghaisas Haripriya Kunchala Darshan Saieesh Ashwin Ashok Naik Ashish Pargaonkar Anuj Sharma Venketesh Sivaramakrishnan Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
description	Abstract Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO datasets to identify features unique to POAG. N9 microglial cells are used to gain mechanistic insights. Our POAG cohort showed elevated ATP in aqueous humor and cytokines in plasma. Metabolomic analysis showed changes in 21 metabolites including Dimethylarginine (DMAG) and activation of tryptophan metabolism in POAG. Analysis of GEO data sets and previously published proteomic data sets bins genes into signaling and metabolic pathways. Pathways from reanalyzed metabolomic data from literature significantly overlapped with those from our POAG data. DMAG modulated purinergic signaling, ATP secretion and cytokine expression were inhibited by N-Ethylmaleimide, NO donors, BAPTA and purinergic receptor inhibitors. ATP induced elevated intracellular calcium level and cytokines expression were inhibited by BAPTA. Metabolomics of cell culture supernatant from ATP treated sets showed metabolic deregulation and activation of tryptophan metabolism. DMAG and ATP induced IDO1/2 and TDO2 were inhibited by N-Ethylmaleimide, sodium nitroprusside and BAPTA. Our data obtained from clinical samples and cell culture studies reveal a strong association of elevated DMAG, ATP, cytokines and activation of tryptophan metabolism with POAG. DMAG mediated ATP signaling, inflammation and metabolic remodeling in microglia might have implications in management of POAG.
format	article
author	Sujith Kumar Pulukool Sai Krishna Srimadh Bhagavatham Vishnu Kannan Piruthivi Sukumar Rajesh Babu Dandamudi Shamika Ghaisas Haripriya Kunchala Darshan Saieesh Ashwin Ashok Naik Ashish Pargaonkar Anuj Sharma Venketesh Sivaramakrishnan
author_facet	Sujith Kumar Pulukool Sai Krishna Srimadh Bhagavatham Vishnu Kannan Piruthivi Sukumar Rajesh Babu Dandamudi Shamika Ghaisas Haripriya Kunchala Darshan Saieesh Ashwin Ashok Naik Ashish Pargaonkar Anuj Sharma Venketesh Sivaramakrishnan
author_sort	Sujith Kumar Pulukool
title	Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
title_short	Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
title_full	Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
title_fullStr	Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
title_full_unstemmed	Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
title_sort	elevated dimethylarginine, atp, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7c8d5e80c6984f2a9a441ababc5e7595
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Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma

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