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Metabonomic analysis of potential biomarkers and drug targets involved in diabetic nephropathy mice.

Wei T, Zhao L, Jia J, Xia H, Du Y, Lin Q, Lin X, Ye X, Yan Z, Gao H - Sci Rep (2015)

Bottom Line: Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN.Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN.Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035 China.

ABSTRACT
Diabetic nephropathy (DN) is one of the lethal manifestations of diabetic systemic microvascular disease. Elucidation of characteristic metabolic alterations during diabetic progression is critical to understand its pathogenesis and identify potential biomarkers and drug targets involved in the disease. In this study, (1)H nuclear magnetic resonance ((1)H NMR)-based metabonomics with correlative analysis was performed to study the characteristic metabolites, as well as the related pathways in urine and kidney samples of db/db diabetic mice, compared with age-matched wildtype mice. The time trajectory plot of db/db mice revealed alterations, in an age-dependent manner, in urinary metabolic profiles along with progression of renal damage and dysfunction. Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN. Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN. Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.

No MeSH data available.


Related in: MedlinePlus

Disturbed metabolic pathways related to pathogenic process of diabetic nephropathy.The metabolite changes detected by 1H NMR urine and kidney analysis and the pathway referenced to the KEGG database show the interrelationship of the identified metabolic pathways involved in the db/db mice. Metabolites in red and green represent increase and decrease in levels, respectively, compared with wildtype mice. Stars represent the potential targets of drugs for diabetic nephropathy.
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f8: Disturbed metabolic pathways related to pathogenic process of diabetic nephropathy.The metabolite changes detected by 1H NMR urine and kidney analysis and the pathway referenced to the KEGG database show the interrelationship of the identified metabolic pathways involved in the db/db mice. Metabolites in red and green represent increase and decrease in levels, respectively, compared with wildtype mice. Stars represent the potential targets of drugs for diabetic nephropathy.

Mentions: The pathway analysis, including the analysis of TCA cycle, glycolysis, methylamine metabolism, purine metabolism, pyrimidine metabolism, and fatty acid β-oxidation, was performed using the KEGG database (http://www.genome.jp/kegg/pathway.html). Results showing alterations in metabolic pathways during the progression of DN are summarized in Fig. 8. The reduced concentrations of methylamine, DMA, TMA, and choline in the db/db mice suggested the down-regulation of the methylamine pathway. The lower levels of 3-HB, acetone, acetoacetate, and acetate indicated reduced or slow fatty acid β-oxidation in the db/db mice. These metabolic changes and the associated pathways provide insights into the mechanisms involved in the development and progression of DN.


Metabonomic analysis of potential biomarkers and drug targets involved in diabetic nephropathy mice.

Wei T, Zhao L, Jia J, Xia H, Du Y, Lin Q, Lin X, Ye X, Yan Z, Gao H - Sci Rep (2015)

Disturbed metabolic pathways related to pathogenic process of diabetic nephropathy.The metabolite changes detected by 1H NMR urine and kidney analysis and the pathway referenced to the KEGG database show the interrelationship of the identified metabolic pathways involved in the db/db mice. Metabolites in red and green represent increase and decrease in levels, respectively, compared with wildtype mice. Stars represent the potential targets of drugs for diabetic nephropathy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493693&req=5

f8: Disturbed metabolic pathways related to pathogenic process of diabetic nephropathy.The metabolite changes detected by 1H NMR urine and kidney analysis and the pathway referenced to the KEGG database show the interrelationship of the identified metabolic pathways involved in the db/db mice. Metabolites in red and green represent increase and decrease in levels, respectively, compared with wildtype mice. Stars represent the potential targets of drugs for diabetic nephropathy.
Mentions: The pathway analysis, including the analysis of TCA cycle, glycolysis, methylamine metabolism, purine metabolism, pyrimidine metabolism, and fatty acid β-oxidation, was performed using the KEGG database (http://www.genome.jp/kegg/pathway.html). Results showing alterations in metabolic pathways during the progression of DN are summarized in Fig. 8. The reduced concentrations of methylamine, DMA, TMA, and choline in the db/db mice suggested the down-regulation of the methylamine pathway. The lower levels of 3-HB, acetone, acetoacetate, and acetate indicated reduced or slow fatty acid β-oxidation in the db/db mice. These metabolic changes and the associated pathways provide insights into the mechanisms involved in the development and progression of DN.

Bottom Line: Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN.Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN.Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035 China.

ABSTRACT
Diabetic nephropathy (DN) is one of the lethal manifestations of diabetic systemic microvascular disease. Elucidation of characteristic metabolic alterations during diabetic progression is critical to understand its pathogenesis and identify potential biomarkers and drug targets involved in the disease. In this study, (1)H nuclear magnetic resonance ((1)H NMR)-based metabonomics with correlative analysis was performed to study the characteristic metabolites, as well as the related pathways in urine and kidney samples of db/db diabetic mice, compared with age-matched wildtype mice. The time trajectory plot of db/db mice revealed alterations, in an age-dependent manner, in urinary metabolic profiles along with progression of renal damage and dysfunction. Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN. Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN. Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.

No MeSH data available.


Related in: MedlinePlus