Renal gene and protein expression signatures for prediction of kidney disease progression.
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-beta1 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 (R(2) = 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.
Ju
Wenjun
W
Dept. of Medicine, Mount Sinai Medical Center, One Gustave L. Levy Pl., Box 1118, New York, NY 10029, USA.
Eichinger
Felix
F
Bitzer
Markus
M
Oh
Jun
J
McWeeney
Shannon
S
Berthier
Celine C
CC
Shedden
Kerby
K
Cohen
Clemens D
CD
Henger
Anna
A
Krick
Stefanie
S
Kopp
Jeffrey B
JB
Stoeckert
Christian J
CJ
Dikman
Steven
S
Schröppel
Bernd
B
Thomas
David B
DB
Schlondorff
Detlef
D
Kretzler
Matthias
M
Böttinger
Erwin P
EP
D000818:Animals; D016000:Cluster Analysis; D018450:Disease Progression; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1