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A molecular signature of proteinuria in glomerulonephritis.

ABSTRACT: 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.

SUBMITTER: Reich HN

PROVIDER: S-EPMC2956647 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A molecular signature of proteinuria in glomerulonephritis.

Reich Heather N HN Tritchler David D Cattran Daniel C DC Herzenberg Andrew M AM Eichinger Felix F Boucherot Anissa A Henger Anna A Berthier Celine C CC Nair Viji V Cohen Clemens D CD Scholey James W JW Kretzler Matthias M

PloS one 20101018 10

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" differentia ...[more]

PMID: 20976140

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Project description:Minimal Change Disease (MCD) is a clinical condition characterized by acute nephrotic syndrome, no evident renal lesions at histology and good response to steroids. However, frequent recurrence of the disease requires additional therapies associated with steroids. Such multi-drug dependence and frequent relapses may cause disease evolution to focal and segmental glomerulosclerosis (FSGS) over time. The differences between the two conditions are not well defined, since molecular mechanisms may be shared by the two diseases. In some cases, genetic analysis can make it possible to distinguish MCD from FSGS; however, there are cases of overlap. Several hypotheses on mechanisms underlying MCD and potential molecular triggers have been proposed. Most studies were conducted on animal models of proteinuria that partially mimic MCD and may be useful to study glomerulosclerosis evolution; however, they do not demonstrate a clear-cut separation between MCD and FSGS. Puromycin Aminonucleoside and Adriamycin nephrosis are models of glomerular oxidative damage, characterized by loss of glomerular basement membrane polyanions resembling MCD at the onset and, at more advanced stages, by glomerulosclerosis resembling FSGS. Also Buffalo/Mna rats present initial lesions of MCD, subsequently evolving to FSGS; this mechanism of renal damage is clearer since this rat strain inherits the unique characteristic of overexpressing Th2 cytokines. In Lipopolysaccharide nephropathy, an immunological condition of renal toxicity linked to B7-1(CD80), mice develop transient proteinuria that lasts a few days. Overall, animal models are useful and necessary considering that they reproduce the evolution from MCD to FSGS that is, in part, due to persistence of proteinuria. The role of T/Treg/Bcells on human MCD has been discussed. Many cytokines, immunomodulatory mechanisms, and several molecules have been defined as a specific cause of proteinuria. However, the hypothesis of a single cell subset or molecule as cause of MCD is not supported by research and an interactive process seems more logical. The implication or interactive role of oxidants, Th2 cytokines, Th17, Tregs, B7-1(CD80), CD40/CD40L, c-Mip, TNF, uPA/suPAR, Angiopoietin-like 4 still awaits a definitive confirmation. Whole genome sequencing studies could help to define specific genetic features that justify a definition of MCD as a "clinical-pathology-genetic entity."

Dataset Information

A molecular signature of proteinuria in glomerulonephritis.

Publications

A molecular signature of proteinuria in glomerulonephritis.

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