期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 27, 期 6, 页码 1702-1713出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2015020225
关键词
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资金
- National Institutes of Health (NIH)/National Institute of Environmental Health Sciences [R01-ES017537]
- American Recovery and Reinvestment Act funds through NIH/National Human Genome Research Institute [RC2-HG005805]
- National Institute of General Medical Sciences [2P50 GM076547]
- Center for Systems Biology [S10RR027584, GM087221]
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases [DK093574]
- NIH [UH3TR000504]
- NIH/National Institute of Environmental Health Sciences [ES017543]
- Innovation in Regulatory Science Award from Burroughs Wellcome Fund [BWF-1012518]
CKD is the gradual, asymptomatic loss of kidney function, but current tests only identify CKD when significant loss has already happened. Several potential biomarkers of CKD have been reported, but none have been approved for preclinical or clinical use. Using RNA sequencing in a mouse model of folic acid induced nephropathy, we identified ten genes that track kidney fibrosis development, the common pathologic finding in patients with CKD. The gene expression of all ten candidates was confirmed to be significantly higher (approximately ten- to 150-fold) in three well established, mechanistically distinct mouse models of kidney fibrosis than in models of nonfibrotic AKI. Protein expression of these genes was also high in the folic acid model and in patients with biopsy-proven kidney fibrosis. mRNA expression of the ten genes increased with increasing severity of kidney fibrosis, decreased in response to therapeutic intervention, and increased only modestly (approximately two- to five-fold) with liver fibrosis in mice and humans, demonstrating specificity for kidney fibrosis. Using targeted selected reaction monitoring mass spectrometry, we detected three of the ten candidates in human urine: cadherin 11 (CDH11), macrophage mannose receptor C1 (MRC1), and phospholipid transfer protein (PLTP). Furthermore, urinary levels of each of these three proteins distinguished patients with CKD (n=53) from healthy individuals (n=53; P<0.05). In summary, we report the identification of urinary CDH11, MRC1, and PLTP as novel noninvasive biomarkers of CKD.
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