title: 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 characteristic of 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.
authors.affiliation: Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Stec
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Suwan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Cody
authors.initials: C
authors.lastname: Stothers
authors.affiliation: Berea College, 1916 CPO, Berea, KY 40404, United States.
authors.forename: Josh
authors.initials: J
authors.lastname: Avance
authors.affiliation: Choctaw Central High School, Philadelphia, MS 39350, United States.
authors.forename: Deon
authors.initials: D
authors.lastname: Denson
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Harris
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: paul.voziyan@vanderbilt.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
mesh_terms: D000156:Aconitic Acid / Q000378:metabolism / Q000652:urine; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000652:urine*; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D006626:Hippurates / Q000378:metabolism / Q000652:urine; D007200:Indican / Q000378:metabolism / Q000652:urine; D007651:Keto Acids / Q000378:metabolism / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010648:Phenylacetates / Q000378:metabolism / Q000652:urine
chemical_list: D006626:Hippurates; D007651:Keto Acids; D010648:Phenylacetates; C026246:4-hydroxyphenylacetate; C022050:phenylacetylglycine; C013082:alpha-ketoisocaproic acid; D000156:Aconitic Acid; D052250:Nitric Oxide Synthase Type III; D007200:Indican; C030514:hippuric acid; D005998:Glycine
keywords: Diabetic nephropathy; Mouse models; Nuclear magnetic resonance; Urinary metabolites