Metzincins and related genes in experimental renal ageing: towards a unifying fibrosis classifier across species

Anagnostopoulou, A., Hans-Peter Marti, James C. Fuscoe, Joshua C. Kwekel and Andreas Scherer 2014. Metzincins and related genes in experimental renal ageing: towards a unifying fibrosis classifier across species. Nephrology Dialysis Transplantation. 29 (6), p. 1177–1185. https://doi.org/10.1093/ndt/gfu027

TitleMetzincins and related genes in experimental renal ageing: towards a unifying fibrosis classifier across species
TypeJournal article
AuthorsAnagnostopoulou, A., Hans-Peter Marti, James C. Fuscoe, Joshua C. Kwekel and Andreas Scherer
Abstract

Background
We have previously described a transcriptomic classifier consisting of metzincins and related genes (MARGS) discriminating kidneys and other organs with or without fibrosis from human biopsies. We now apply our MARGS-based algorithm to a rat model of age-associated interstitial renal fibrosis.

Methods
Untreated Fisher 344 rats (n = 76) were sacrificed between 2 to 104 weeks of age. For gene expression studies, we used single colour (Cy3) Agilent Whole Rat Genome 4 × 44k microarrays; 4–5 animals of each sex were profiled at each of the following ages: 2, 5, 6, 8, 15, 21, 78 and 104 weeks. Intensity data were subjected to variance stabilization (www.Partek.com). Data were analysed with ANOVA and other statistical methods.

Results
Sixty MARGS were differentially expressed across age groups. More MARGS were differentially expressed in older males than in older females. Principal component analysis showed gene expression induced segregation of age groups by sex from 6 to 104 weeks of age. The expression level of MMP7 correlated best with fibrosis grade. Severity of fibrosis was determined in 20 animals at 78 and 104 weeks of age. Expression values of 15 of 19 genes of the original classifier present on the Agilent array, in conjunction with linear discriminant analysis, was sufficient to correctly classify these 20 samples into non-fibrosis and fibrosis. Overrepresentation of MMP2 protein and CD44 protein in fibrosis was confirmed by immunofluorescence.

Conclusions
Based on these results and our previous work, the MARGS classifier represents a cross-organ and cross-species classifier of fibrosis irrespective of aetiology. This finding provides evidence for a common pathway leading to fibrosis and will help to design a PCR-based clinical test.

Keywordsageing
metzincins
matrix metalloproteinases
classifier
fibrosis
CD44
JournalNephrology Dialysis Transplantation
Journal citation29 (6), p. 1177–1185
ISSN1460-2385
0931-0509
Year2014
PublisherOxford Academic
Digital Object Identifier (DOI)https://doi.org/10.1093/ndt/gfu027
Web address (URL)http://dx.doi.org/10.1093/ndt/gfu027
Publication dates
PublishedJun 2014

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