Cargando…
Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies
BACKGROUND: Human glomerulonephritis (GN)—membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN), as well as diabetic nephropathy (DN) are leading causes of chronic kidney disease. In these glomerulopathies, distinct stimuli disrupt metabolic pathways in gl...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10042326/ https://www.ncbi.nlm.nih.gov/pubmed/36993805 http://dx.doi.org/10.3389/fmed.2023.1122328 |
_version_ | 1784912908414615552 |
---|---|
author | Chung, Chen-Fang Papillon, Joan Navarro-Betancourt, José R. Guillemette, Julie Bhope, Ameya Emad, Amin Cybulsky, Andrey V. |
author_facet | Chung, Chen-Fang Papillon, Joan Navarro-Betancourt, José R. Guillemette, Julie Bhope, Ameya Emad, Amin Cybulsky, Andrey V. |
author_sort | Chung, Chen-Fang |
collection | PubMed |
description | BACKGROUND: Human glomerulonephritis (GN)—membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN), as well as diabetic nephropathy (DN) are leading causes of chronic kidney disease. In these glomerulopathies, distinct stimuli disrupt metabolic pathways in glomerular cells. Other pathways, including the endoplasmic reticulum (ER) unfolded protein response (UPR) and autophagy, are activated in parallel to attenuate cell injury or promote repair. METHODS: We used publicly available datasets to examine gene transcriptional pathways in glomeruli of human GN and DN and to identify drugs. RESULTS: We demonstrate that there are many common genes upregulated in MN, FSGS, IgAN, and DN. Furthermore, these glomerulopathies were associated with increased expression of ER/UPR and autophagy genes, a significant number of which were shared. Several candidate drugs for treatment of glomerulopathies were identified by relating gene expression signatures of distinct drugs in cell culture with the ER/UPR and autophagy genes upregulated in the glomerulopathies (“connectivity mapping”). Using a glomerular cell culture assay that correlates with glomerular damage in vivo, we showed that one candidate drug – neratinib (an epidermal growth factor receptor inhibitor) is cytoprotective. CONCLUSION: The UPR and autophagy are activated in multiple types of glomerular injury. Connectivity mapping identified candidate drugs that shared common signatures with ER/UPR and autophagy genes upregulated in glomerulopathies, and one of these drugs attenuated injury of glomerular cells. The present study opens the possibility for modulating the UPR or autophagy pharmacologically as therapy for GN. |
format | Online Article Text |
id | pubmed-10042326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100423262023-03-28 Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies Chung, Chen-Fang Papillon, Joan Navarro-Betancourt, José R. Guillemette, Julie Bhope, Ameya Emad, Amin Cybulsky, Andrey V. Front Med (Lausanne) Medicine BACKGROUND: Human glomerulonephritis (GN)—membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN), as well as diabetic nephropathy (DN) are leading causes of chronic kidney disease. In these glomerulopathies, distinct stimuli disrupt metabolic pathways in glomerular cells. Other pathways, including the endoplasmic reticulum (ER) unfolded protein response (UPR) and autophagy, are activated in parallel to attenuate cell injury or promote repair. METHODS: We used publicly available datasets to examine gene transcriptional pathways in glomeruli of human GN and DN and to identify drugs. RESULTS: We demonstrate that there are many common genes upregulated in MN, FSGS, IgAN, and DN. Furthermore, these glomerulopathies were associated with increased expression of ER/UPR and autophagy genes, a significant number of which were shared. Several candidate drugs for treatment of glomerulopathies were identified by relating gene expression signatures of distinct drugs in cell culture with the ER/UPR and autophagy genes upregulated in the glomerulopathies (“connectivity mapping”). Using a glomerular cell culture assay that correlates with glomerular damage in vivo, we showed that one candidate drug – neratinib (an epidermal growth factor receptor inhibitor) is cytoprotective. CONCLUSION: The UPR and autophagy are activated in multiple types of glomerular injury. Connectivity mapping identified candidate drugs that shared common signatures with ER/UPR and autophagy genes upregulated in glomerulopathies, and one of these drugs attenuated injury of glomerular cells. The present study opens the possibility for modulating the UPR or autophagy pharmacologically as therapy for GN. Frontiers Media S.A. 2023-03-13 /pmc/articles/PMC10042326/ /pubmed/36993805 http://dx.doi.org/10.3389/fmed.2023.1122328 Text en Copyright © 2023 Chung, Papillon, Navarro-Betancourt, Guillemette, Bhope, Emad and Cybulsky. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Chung, Chen-Fang Papillon, Joan Navarro-Betancourt, José R. Guillemette, Julie Bhope, Ameya Emad, Amin Cybulsky, Andrey V. Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
title | Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
title_full | Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
title_fullStr | Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
title_full_unstemmed | Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
title_short | Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
title_sort | analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10042326/ https://www.ncbi.nlm.nih.gov/pubmed/36993805 http://dx.doi.org/10.3389/fmed.2023.1122328 |
work_keys_str_mv | AT chungchenfang analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies AT papillonjoan analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies AT navarrobetancourtjoser analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies AT guillemettejulie analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies AT bhopeameya analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies AT emadamin analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies AT cybulskyandreyv analysisofgeneexpressionanduseofconnectivitymappingtoidentifydrugsfortreatmentofhumanglomerulopathies |