Alterations of urinary metabolite profile in model diabetic nephropathy

Abstract

Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelial nitric oxide synthase (eNOS) knock-out mice develop major renal lesions found in human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS−/− C57BLKS and eNOS−/− C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis-aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS−/− C57BLKS and eNOS−/− C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be useful new tools in metabolomic studies relevant to human pathology.

Identification of a High-Affinity Pyruvate Receptor in Escherichia coli

“…6A). Both pyruvate and L-serine are present in human and murine urine, and levels are elevated in diabetic populations 21–23 . Given that BtsS/BtsR responds directly to extracellular pyruvate levels and indirectly to L-serine, we asked whether BtsS/BtsR is active in the bladder lumen during acute and chronic UTI.

Figure 6BtsS/BtsR importance during urinary tract infection.

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Urine metabolites are associated with glomerular lesions in type 2 diabetes

“…Aconitic acid excretion is also influenced by pH and hypokalemia due to changes in the activity of cortical aconitase (Demigné et al 2004). Contradictory findings are reported regarding urine concentrations of TCA intermediates in murine models of DKD (Li et al 2013; Stec et al 2015). Like the SCFAs, lower TCA cycle intermediates were associated with loss of filtration surface and with mesangial expansion in the present study.…”

Metabolomics and renal disease

“…Urine metabolite profiles and their response to AMPK activation in this model, however, were not assessed. Using NMR, Stec et al found decreased levels of several urine metabolites in models of type 1 ( eNOS −/− mice treated with streptozotocin) and type 2 diabetes ( eNOS−/− db/db mice) compared to controls [33], although without significant overlap (aside from aconitate) with the human findings described above. Whether these differences reflect the different platforms used, or whether mouse models can faithfully recapitulate the metabolite signatures of human kidney disease is an area of ongoing study [34].…”