TY - JOUR
T1 - RNA sequencing identifies novel translational biomarkers of kidney fibrosis
AU - Craciun, Florin L.
AU - Bijol, Vanesa
AU - Ajay, Amrendra K.
AU - Rao, Poornima
AU - Kumar, Ramya K.
AU - Hutchinson, John
AU - Hofmann, Oliver
AU - Joshi, Nikita
AU - Luyendyk, James P.
AU - Kusebauch, Ulrike
AU - Moss, Christopher L.
AU - Srivastava, Anand
AU - Himmelfarb, Jonathan
AU - Waikar, Sushrut S.
AU - Moritz, Robert L.
AU - Vaidya, Vishal S.
N1 - Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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 acidinduced 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 acidmodel and in patients with biopsy-proven kidney fibrosis.mRNAexpression 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.
AB - 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 acidinduced 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 acidmodel and in patients with biopsy-proven kidney fibrosis.mRNAexpression 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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U2 - 10.1681/ASN.2015020225
DO - 10.1681/ASN.2015020225
M3 - Article
C2 - 26449608
AN - SCOPUS:84979706129
VL - 27
SP - 1702
EP - 1713
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 6
ER -