Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration

Sodium glucose cotransporter, type 2 inhibitors, such as Empagliflozin, are protective of the kidneys by unclear mechanisms. Our aim was to determine how Empagliflozin affected kidney cortical metabolome and lipidome in mice. Adult male TALLYHO mice (prone to obesity) were treated with a high-milk-f...

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Main Authors: Surabhi Bangarbale, Blythe D. Shepard, Shivani Bansal, Meth M. Jayatilake, Ryan Kurtz, Moshe Levi, Carolyn M. Ecelbarger
Format: Article
Language:English
Published: MDPI AG 2022-08-01
Series:Biomolecules
Subjects:
Online Access:https://www.mdpi.com/2218-273X/12/9/1176
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author Surabhi Bangarbale
Blythe D. Shepard
Shivani Bansal
Meth M. Jayatilake
Ryan Kurtz
Moshe Levi
Carolyn M. Ecelbarger
author_facet Surabhi Bangarbale
Blythe D. Shepard
Shivani Bansal
Meth M. Jayatilake
Ryan Kurtz
Moshe Levi
Carolyn M. Ecelbarger
author_sort Surabhi Bangarbale
collection DOAJ
description Sodium glucose cotransporter, type 2 inhibitors, such as Empagliflozin, are protective of the kidneys by unclear mechanisms. Our aim was to determine how Empagliflozin affected kidney cortical metabolome and lipidome in mice. Adult male TALLYHO mice (prone to obesity) were treated with a high-milk-fat diet, or this diet containing Empagliflozin (0.01%), for 8 weeks. Targeted and untargeted metabolomics and lipidomics were conducted on kidney cortex by liquid chromatography followed by tandem mass-spectroscopy. Metabolites were statistically analyzed by MetaboAnalyst 5.0, LipidSig (lipid species only) and/or CEU Mass Mediator (untargeted annotation). In general, volcano plotting revealed oppositely skewed patterns for targeted metabolites (primarily hydrophilic) and lipids (hydrophobic) in that polar metabolites showed a larger number of decreased species, while non-polar (lipids) had a greater number of increased species (>20% changed and/or raw <i>p</i>-value < 0.05). The top three pathways regulated by Empagliflozin were urea cycle, spermine/spermidine biosynthesis, and aspartate metabolism, with an amino acid network being highly affected, with 14 of 20 classic amino acids down-regulated. Out of 75 changed polar metabolites, only three were up-regulated, i.e., flavin mononucleotide (FMN), uridine, and ureidosuccinic acid. Both FMN and uridine have been shown to be protective of the kidney. Scrutiny of metabolites of glycolysis/gluconeogenesis/Krebs cycle revealed a 20–45% reduction in several species, including phosphoenolpyruvate (PEP), succinate, and malic acid. In contrast, although overall lipid quantity was not higher, several lipid species were increased by EMPA, including those of the classes, phosphatidic acids, phosphatidylcholines, and carnitines. Overall, these analyses suggest a protection from extensive metabolic load and the corresponding oxidative stress with EMPA in kidney. This may be in response to reduced energy demands of the proximal tubule as a result of inhibition of transport and/or differences in metabolic pools available for metabolism.
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spelling doaj.art-ebc3df4bd15947cab1cf34334de3f4252023-11-23T15:14:11ZengMDPI AGBiomolecules2218-273X2022-08-01129117610.3390/biom12091176Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular RespirationSurabhi Bangarbale0Blythe D. Shepard1Shivani Bansal2Meth M. Jayatilake3Ryan Kurtz4Moshe Levi5Carolyn M. Ecelbarger6Department of Medicine, Georgetown University, Washington, DC 20057, USADepartment of Human Science, Georgetown University, Washington, DC 20057, USAProteomic & Metabolomics Shared Resource, Georgetown University, Washington, DC 20057, USAProteomic & Metabolomics Shared Resource, Georgetown University, Washington, DC 20057, USADepartment of Human Science, Georgetown University, Washington, DC 20057, USADepartment of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057, USADepartment of Medicine, Georgetown University, Washington, DC 20057, USASodium glucose cotransporter, type 2 inhibitors, such as Empagliflozin, are protective of the kidneys by unclear mechanisms. Our aim was to determine how Empagliflozin affected kidney cortical metabolome and lipidome in mice. Adult male TALLYHO mice (prone to obesity) were treated with a high-milk-fat diet, or this diet containing Empagliflozin (0.01%), for 8 weeks. Targeted and untargeted metabolomics and lipidomics were conducted on kidney cortex by liquid chromatography followed by tandem mass-spectroscopy. Metabolites were statistically analyzed by MetaboAnalyst 5.0, LipidSig (lipid species only) and/or CEU Mass Mediator (untargeted annotation). In general, volcano plotting revealed oppositely skewed patterns for targeted metabolites (primarily hydrophilic) and lipids (hydrophobic) in that polar metabolites showed a larger number of decreased species, while non-polar (lipids) had a greater number of increased species (>20% changed and/or raw <i>p</i>-value < 0.05). The top three pathways regulated by Empagliflozin were urea cycle, spermine/spermidine biosynthesis, and aspartate metabolism, with an amino acid network being highly affected, with 14 of 20 classic amino acids down-regulated. Out of 75 changed polar metabolites, only three were up-regulated, i.e., flavin mononucleotide (FMN), uridine, and ureidosuccinic acid. Both FMN and uridine have been shown to be protective of the kidney. Scrutiny of metabolites of glycolysis/gluconeogenesis/Krebs cycle revealed a 20–45% reduction in several species, including phosphoenolpyruvate (PEP), succinate, and malic acid. In contrast, although overall lipid quantity was not higher, several lipid species were increased by EMPA, including those of the classes, phosphatidic acids, phosphatidylcholines, and carnitines. Overall, these analyses suggest a protection from extensive metabolic load and the corresponding oxidative stress with EMPA in kidney. This may be in response to reduced energy demands of the proximal tubule as a result of inhibition of transport and/or differences in metabolic pools available for metabolism.https://www.mdpi.com/2218-273X/12/9/1176SGLT2gluconeogenesisoxidative phosphorylationrenalproximal tubule
spellingShingle Surabhi Bangarbale
Blythe D. Shepard
Shivani Bansal
Meth M. Jayatilake
Ryan Kurtz
Moshe Levi
Carolyn M. Ecelbarger
Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
Biomolecules
SGLT2
gluconeogenesis
oxidative phosphorylation
renal
proximal tubule
title Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
title_full Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
title_fullStr Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
title_full_unstemmed Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
title_short Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
title_sort renal metabolome in obese mice treated with empagliflozin suggests a reduction in cellular respiration
topic SGLT2
gluconeogenesis
oxidative phosphorylation
renal
proximal tubule
url https://www.mdpi.com/2218-273X/12/9/1176
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