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, 1H nuclear magnetic resonance (1H 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.
Highlights
Diabetic nephropathy (DN) is one of the lethal manifestations of diabetic systemic microvascular disease
With the goals of discovering specific biomarkers of disease progression, identifying perturbed metabolic pathways associated with the pathogenesis of the disease, and discovering potential drug targets, the NMR-based metabonomics with correlative analysis was performed to study the metabolic alterations in the urine and renal tissue samples obtained from the db/db mice
Diffuse mesangial matrix expansion and thickening of the glomerular capillary basement membranes observed in the kidney tissues of 17-week-old db/db mice are consistent with previous reports on chronic renal injury in diabetic animals[12]
Summary
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. To comprehensively profile the changes in metabolite levels associated with the progression of DN, we used the db/db mouse, a well-established animal model of type 2 diabetes, which develops features of DN and renal damage with age[12]. With the goals of discovering specific biomarkers of disease progression, identifying perturbed metabolic pathways associated with the pathogenesis of the disease, and discovering potential drug targets, the NMR-based metabonomics with correlative analysis was performed to study the metabolic alterations in the urine and renal tissue samples obtained from the db/db mice
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