The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study.
We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-β, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml·min(-1)·1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-β-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans.
Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106, USA. mss5@case.edu
Michael S
MS
Simonson
Margaret
M
Tiktin
Sara M
SM
Debanne
Mahboob
M
Rahman
Bruce
B
Berger
Donald
D
Hricik
Faramarz
F
Ismail-Beigi
D000209:Acute-Phase Proteins / Q000652:urine; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000652:urine*; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000652:urine*; D003924:Diabetes Mellitus, Type 2 / Q000652:urine*; D003928:Diabetic Nephropathies / Q000652:urine*; D019332:Endothelin-1 / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate; D055436:Growth Differentiation Factor 15 / Q000652:urine; D006801:Humans; D007118:Immunoassay; D015850:Interleukin-6 / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D051379:Mice; D008875:Middle Aged; D010865:Pilot Projects; D011518:Proto-Oncogene Proteins / Q000652:urine; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000652:urine
D000209:Acute-Phase Proteins; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019332:Endothelin-1; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C508600:IL6 protein, human; D015850:Interleukin-6; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta