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Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examin...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997785/ https://www.ncbi.nlm.nih.gov/pubmed/35406730 http://dx.doi.org/10.3390/cells11071166 |
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author | Collins, Kimberly S. Eadon, Michael T. Cheng, Ying-Hua Barwinska, Daria Melo Ferreira, Ricardo McCarthy, Thomas W. Janosevic, Danielle Syed, Farooq Maier, Bernhard El-Achkar, Tarek M. Kelly, Katherine J. Phillips, Carrie L. Hato, Takashi Sutton, Timothy A. Dagher, Pierre C. |
author_facet | Collins, Kimberly S. Eadon, Michael T. Cheng, Ying-Hua Barwinska, Daria Melo Ferreira, Ricardo McCarthy, Thomas W. Janosevic, Danielle Syed, Farooq Maier, Bernhard El-Achkar, Tarek M. Kelly, Katherine J. Phillips, Carrie L. Hato, Takashi Sutton, Timothy A. Dagher, Pierre C. |
author_sort | Collins, Kimberly S. |
collection | PubMed |
description | Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography–mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD. |
format | Online Article Text |
id | pubmed-8997785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89977852022-04-12 Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease Collins, Kimberly S. Eadon, Michael T. Cheng, Ying-Hua Barwinska, Daria Melo Ferreira, Ricardo McCarthy, Thomas W. Janosevic, Danielle Syed, Farooq Maier, Bernhard El-Achkar, Tarek M. Kelly, Katherine J. Phillips, Carrie L. Hato, Takashi Sutton, Timothy A. Dagher, Pierre C. Cells Article Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography–mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD. MDPI 2022-03-30 /pmc/articles/PMC8997785/ /pubmed/35406730 http://dx.doi.org/10.3390/cells11071166 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Collins, Kimberly S. Eadon, Michael T. Cheng, Ying-Hua Barwinska, Daria Melo Ferreira, Ricardo McCarthy, Thomas W. Janosevic, Danielle Syed, Farooq Maier, Bernhard El-Achkar, Tarek M. Kelly, Katherine J. Phillips, Carrie L. Hato, Takashi Sutton, Timothy A. Dagher, Pierre C. Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease |
title | Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease |
title_full | Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease |
title_fullStr | Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease |
title_full_unstemmed | Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease |
title_short | Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease |
title_sort | alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997785/ https://www.ncbi.nlm.nih.gov/pubmed/35406730 http://dx.doi.org/10.3390/cells11071166 |
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