Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease
Metabolic reprogramming is a hallmark of diabetic kidney disease (DKD); nutrient overload leads to increased production of metabolic byproducts that may become toxic at high levels. One metabolic byproduct may be 2-hydroxyglutarate (2-HG), a metabolite with many regulatory functions that exists in b...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Metabolites |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-1989/11/8/469 |
| _version_ | 1827684797365878784 |
|---|---|
| author | Judy Baek Subramaniam Pennathur |
| author_facet | Judy Baek Subramaniam Pennathur |
| author_sort | Judy Baek |
| collection | DOAJ |
| description | Metabolic reprogramming is a hallmark of diabetic kidney disease (DKD); nutrient overload leads to increased production of metabolic byproducts that may become toxic at high levels. One metabolic byproduct may be 2-hydroxyglutarate (2-HG), a metabolite with many regulatory functions that exists in both enantiomeric forms physiologically. We quantitatively determined the levels of L and D-2HG enantiomers in the urine, plasma, and kidney cortex of <i>db</i>/<i>db</i> mice, a pathophysiologically relevant murine model of type 2 diabetes and DKD. We found increased fractional excretion of both L and D-2HG enantiomers, suggesting increased tubular secretion and/or production of the two metabolites in DKD. Quantitation of TCA cycle metabolites in <i>db</i>/<i>db</i> cortex suggests that TCA cycle overload and an increase in 2-HG precursor substrate, α-ketoglutarate, drive the increased L and D-2HG production in DKD. In conclusion, we demonstrated increased 2-HG enantiomer production and urinary excretion in murine type 2 DKD, which may contribute to metabolic reprogramming and progression of diabetic kidney disease. |
| first_indexed | 2024-03-10T08:36:14Z |
| format | Article |
| id | doaj.art-7b3b8d79b4fe4f0e8b609cc64fb9a556 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T08:36:14Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-7b3b8d79b4fe4f0e8b609cc64fb9a5562023-11-22T08:38:43ZengMDPI AGMetabolites2218-19892021-07-0111846910.3390/metabo11080469Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney DiseaseJudy Baek0Subramaniam Pennathur1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USADepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USAMetabolic reprogramming is a hallmark of diabetic kidney disease (DKD); nutrient overload leads to increased production of metabolic byproducts that may become toxic at high levels. One metabolic byproduct may be 2-hydroxyglutarate (2-HG), a metabolite with many regulatory functions that exists in both enantiomeric forms physiologically. We quantitatively determined the levels of L and D-2HG enantiomers in the urine, plasma, and kidney cortex of <i>db</i>/<i>db</i> mice, a pathophysiologically relevant murine model of type 2 diabetes and DKD. We found increased fractional excretion of both L and D-2HG enantiomers, suggesting increased tubular secretion and/or production of the two metabolites in DKD. Quantitation of TCA cycle metabolites in <i>db</i>/<i>db</i> cortex suggests that TCA cycle overload and an increase in 2-HG precursor substrate, α-ketoglutarate, drive the increased L and D-2HG production in DKD. In conclusion, we demonstrated increased 2-HG enantiomer production and urinary excretion in murine type 2 DKD, which may contribute to metabolic reprogramming and progression of diabetic kidney disease.https://www.mdpi.com/2218-1989/11/8/469diabetic kidney diseasebiomarkermitochondria2-hydroxyglutarateTCA cycle |
| spellingShingle | Judy Baek Subramaniam Pennathur Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease Metabolites diabetic kidney disease biomarker mitochondria 2-hydroxyglutarate TCA cycle |
| title | Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease |
| title_full | Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease |
| title_fullStr | Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease |
| title_full_unstemmed | Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease |
| title_short | Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease |
| title_sort | urinary 2 hydroxyglutarate enantiomers are markedly elevated in a murine model of type 2 diabetic kidney disease |
| topic | diabetic kidney disease biomarker mitochondria 2-hydroxyglutarate TCA cycle |
| url | https://www.mdpi.com/2218-1989/11/8/469 |
| work_keys_str_mv | AT judybaek urinary2hydroxyglutarateenantiomersaremarkedlyelevatedinamurinemodeloftype2diabetickidneydisease AT subramaniampennathur urinary2hydroxyglutarateenantiomersaremarkedlyelevatedinamurinemodeloftype2diabetickidneydisease |