TY - JOUR
T1 - Renal gene and protein expression signatures for prediction of kidney disease progression
AU - Ju, Wenjun
AU - Eichinger, Felix
AU - Bitzer, Markus
AU - Oh, Jun
AU - McWeeney, Shannon
AU - Berthier, Celine C.
AU - Shedden, Kerby
AU - Cohen, Clemens D.
AU - Henger, Anna
AU - Krick, Stefanie
AU - Kopp, Jeffrey B.
AU - Stoeckert, Christian J.
AU - Dikman, Steven
AU - Schröppel, Bernd
AU - Thomas, David B.
AU - Schlondorff, Detlef
AU - Kretzler, Matthias
AU - Böttinger, Erwin P.
PY - 2009/6
Y1 - 2009/6
N2 - Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-β1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R2 = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans.
AB - Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-β1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R2 = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans.
UR - http://www.scopus.com/inward/record.url?scp=67049118905&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2009.080888
DO - 10.2353/ajpath.2009.080888
M3 - Article
C2 - 19465643
AN - SCOPUS:67049118905
SN - 0002-9440
VL - 174
SP - 2073
EP - 2085
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -