A molecular signature of proteinuria in glomerulonephritis.
Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 "albumin-regulated genes" differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n = 25) could be distinguished from those of control subjects (n = 6) based solely upon the expression of these 231 "albumin-regulated genes." The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that all forms of primary glomerulonephritis (n = 33) can be distinguished from controls (n = 21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis.
Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada. hreich@uhnresearch.on.ca
Heather N
HN
Reich
David
D
Tritchler
Daniel C
DC
Cattran
Andrew M
AM
Herzenberg
Felix
F
Eichinger
Anissa
A
Boucherot
Anna
A
Henger
Celine C
CC
Berthier
Viji
V
Nair
Clemens D
CD
Cohen
James W
JW
Scholey
Matthias
M
Kretzler
D000418:Albumins / Q000235:genetics; D001706:Biopsy; D020869:Gene Expression Profiling; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011507:Proteinuria / Q000235:genetics* / Q000473:pathology
D000418:Albumins