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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

Quantitative analysis of urinary metabolites.Relative abundances of metabolites obtained from 1H NMR spectra of urine samples collected from the db/db mice and the wildtype mice at 9-wk, 11-wk, 13-wk, 15-wk and 17-wk, respectively. Keys: MNA, 1-methylnicotinamide; *P < 0.05 and **P < 0.01 compared with age-matched wildtype mice; #P < 0.05 and ##P < 0.01 compared with the db/db mice at 9-wk.
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f4: Quantitative analysis of urinary metabolites.Relative abundances of metabolites obtained from 1H NMR spectra of urine samples collected from the db/db mice and the wildtype mice at 9-wk, 11-wk, 13-wk, 15-wk and 17-wk, respectively. Keys: MNA, 1-methylnicotinamide; *P < 0.05 and **P < 0.01 compared with age-matched wildtype mice; #P < 0.05 and ##P < 0.01 compared with the db/db mice at 9-wk.

Mentions: The changes in key metabolites from the onset to the progression of the disease are shown in Fig. 4. Compared with the wildtype mice, elevated levels of several TCA-cycle intermediates (2-oxoglutarate, citrate, cis-aconitate, and fumarate) were evident in the samples from db/db mice. At 9 weeks, there were no obvious changes in citrate and cis-aconitate levels between the wildtype and db/db mice. However, their levels were higher during the middle and late stages of DN (Fig. 4A). 2-oxoglutarate and fumarate levels were high at the early stage of DN and were partly restored to control levels during the late stages. Pyruvate, which is produced by glucose metabolism, was reduced during the progression of DN, with a drastic reduction seen at 17 weeks in db/db mice. Additionally, lactate levels were increased in db/db animals of 9 weeks (Fig. 4B). These changes indicated altered glucose metabolism during the development and progression of DN. Compared with the wildtype mice, creatinine levels, which reflect renal function, were lower in the db/db mice throughout the experimental period. Allantoin, 1-methylnicotinamide (MNA), and hippurate were altered in an age-dependent manner. For example, at the age of 13 weeks, hippurate levels were elevated and reached a maximum at 17 weeks in the db/db mice, suggesting a strong correlation between hippurate concentration and progression of the disease (Fig. 4C). The lipid byproducts, acetate, 3-hydroxybutyrate (3-HB), and acetoacetate, were reduced in the db/db mice throughout the experimental period, suggesting reduced lipid metabolism in DN (Fig. 4D).


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)

Quantitative analysis of urinary metabolites.Relative abundances of metabolites obtained from 1H NMR spectra of urine samples collected from the db/db mice and the wildtype mice at 9-wk, 11-wk, 13-wk, 15-wk and 17-wk, respectively. Keys: MNA, 1-methylnicotinamide; *P < 0.05 and **P < 0.01 compared with age-matched wildtype mice; #P < 0.05 and ##P < 0.01 compared with the db/db mice at 9-wk.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Quantitative analysis of urinary metabolites.Relative abundances of metabolites obtained from 1H NMR spectra of urine samples collected from the db/db mice and the wildtype mice at 9-wk, 11-wk, 13-wk, 15-wk and 17-wk, respectively. Keys: MNA, 1-methylnicotinamide; *P < 0.05 and **P < 0.01 compared with age-matched wildtype mice; #P < 0.05 and ##P < 0.01 compared with the db/db mice at 9-wk.
Mentions: The changes in key metabolites from the onset to the progression of the disease are shown in Fig. 4. Compared with the wildtype mice, elevated levels of several TCA-cycle intermediates (2-oxoglutarate, citrate, cis-aconitate, and fumarate) were evident in the samples from db/db mice. At 9 weeks, there were no obvious changes in citrate and cis-aconitate levels between the wildtype and db/db mice. However, their levels were higher during the middle and late stages of DN (Fig. 4A). 2-oxoglutarate and fumarate levels were high at the early stage of DN and were partly restored to control levels during the late stages. Pyruvate, which is produced by glucose metabolism, was reduced during the progression of DN, with a drastic reduction seen at 17 weeks in db/db mice. Additionally, lactate levels were increased in db/db animals of 9 weeks (Fig. 4B). These changes indicated altered glucose metabolism during the development and progression of DN. Compared with the wildtype mice, creatinine levels, which reflect renal function, were lower in the db/db mice throughout the experimental period. Allantoin, 1-methylnicotinamide (MNA), and hippurate were altered in an age-dependent manner. For example, at the age of 13 weeks, hippurate levels were elevated and reached a maximum at 17 weeks in the db/db mice, suggesting a strong correlation between hippurate concentration and progression of the disease (Fig. 4C). The lipid byproducts, acetate, 3-hydroxybutyrate (3-HB), and acetoacetate, were reduced in the db/db mice throughout the experimental period, suggesting reduced lipid metabolism in DN (Fig. 4D).

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