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Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice
Many clinical studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have renoprotective properties by ameliorating albuminuria and increasing glomerular filtration rate in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) by lowering ectopic li...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921774/ https://www.ncbi.nlm.nih.gov/pubmed/35299724 http://dx.doi.org/10.3389/fphar.2021.777395 |
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author | Yeung, Martin Ho Yin Leung, Ka Long Choi, Lai Yuen Yoo, Jung Sun Yung, Susan So, Pui-Kin Wong, Chi-Ming |
author_facet | Yeung, Martin Ho Yin Leung, Ka Long Choi, Lai Yuen Yoo, Jung Sun Yung, Susan So, Pui-Kin Wong, Chi-Ming |
author_sort | Yeung, Martin Ho Yin |
collection | PubMed |
description | Many clinical studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have renoprotective properties by ameliorating albuminuria and increasing glomerular filtration rate in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) by lowering ectopic lipid accumulation in the kidney. However, the mechanism of GLP-1RAs was hitherto unknown. Here, we conducted an unbiased lipidomic analysis using ultra-high-performance liquid chromatography/electrospray ionization-quadrupole time-of-flight mass spectrometry (UHPLC/ESI-Q-TOF-MS) and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to reveal the changes of lipid composition and distribution in the kidneys of high-fat diet-fed mice after treatment with a long-acting GLP-1RA dulaglutide for 4 weeks. Treatment of dulaglutide dramatically improved hyperglycemia and albuminuria, but there was no substantial improvement in dyslipidemia and ectopic lipid accumulation in the kidney as compared with controls. Intriguingly, treatment of dulaglutide increases the level of an essential phospholipid constituent of inner mitochondrial membrane cardiolipin at the cortex region of the kidneys by inducing the expression of key cardiolipin biosynthesis enzymes. Previous studies demonstrated that lowered renal cardiolipin level impairs kidney function via mitochondrial damage. Our untargeted lipidomic analysis presents evidence for a new mechanism of how GLP-1RAs stimulate mitochondrial bioenergetics via increasing cardiolipin level and provides new insights into the therapeutic potential of GLP-1RAs in mitochondrial-related diseases. |
format | Online Article Text |
id | pubmed-8921774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89217742022-03-16 Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice Yeung, Martin Ho Yin Leung, Ka Long Choi, Lai Yuen Yoo, Jung Sun Yung, Susan So, Pui-Kin Wong, Chi-Ming Front Pharmacol Pharmacology Many clinical studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have renoprotective properties by ameliorating albuminuria and increasing glomerular filtration rate in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) by lowering ectopic lipid accumulation in the kidney. However, the mechanism of GLP-1RAs was hitherto unknown. Here, we conducted an unbiased lipidomic analysis using ultra-high-performance liquid chromatography/electrospray ionization-quadrupole time-of-flight mass spectrometry (UHPLC/ESI-Q-TOF-MS) and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to reveal the changes of lipid composition and distribution in the kidneys of high-fat diet-fed mice after treatment with a long-acting GLP-1RA dulaglutide for 4 weeks. Treatment of dulaglutide dramatically improved hyperglycemia and albuminuria, but there was no substantial improvement in dyslipidemia and ectopic lipid accumulation in the kidney as compared with controls. Intriguingly, treatment of dulaglutide increases the level of an essential phospholipid constituent of inner mitochondrial membrane cardiolipin at the cortex region of the kidneys by inducing the expression of key cardiolipin biosynthesis enzymes. Previous studies demonstrated that lowered renal cardiolipin level impairs kidney function via mitochondrial damage. Our untargeted lipidomic analysis presents evidence for a new mechanism of how GLP-1RAs stimulate mitochondrial bioenergetics via increasing cardiolipin level and provides new insights into the therapeutic potential of GLP-1RAs in mitochondrial-related diseases. Frontiers Media S.A. 2022-03-01 /pmc/articles/PMC8921774/ /pubmed/35299724 http://dx.doi.org/10.3389/fphar.2021.777395 Text en Copyright © 2022 Yeung, Leung, Choi, Yoo, Yung, So and Wong. 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 | Pharmacology Yeung, Martin Ho Yin Leung, Ka Long Choi, Lai Yuen Yoo, Jung Sun Yung, Susan So, Pui-Kin Wong, Chi-Ming Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice |
title | Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice |
title_full | Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice |
title_fullStr | Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice |
title_full_unstemmed | Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice |
title_short | Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice |
title_sort | lipidomic analysis reveals the protection mechanism of glp-1 analogue dulaglutide on high-fat diet-induced chronic kidney disease in mice |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921774/ https://www.ncbi.nlm.nih.gov/pubmed/35299724 http://dx.doi.org/10.3389/fphar.2021.777395 |
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