Renal Fibrosis mRNA Classifier: Validation in Experimental Lithium-Induced Interstitial Fibrosis in the Rat Kidney

Autor: Robert J. Walker, Hans-Peter Marti, Catherine J Leader, Andreas Scherer, Jennifer J. Bedford, Aaron Jeffs, John P. Leader
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Pathology
Microarrays
030232 urology & nephrology
lcsh:Medicine
Gene Expression
Kidney
0302 clinical medicine
Mathematical and Statistical Techniques
Fibrosis
Gene expression
Medicine and Health Sciences
lcsh:Science
Oligonucleotide Array Sequence Analysis
Staining
Principal Component Analysis
Multidisciplinary
Immunohistochemistry
Up-Regulation
Chemistry
medicine.anatomical_structure
Hyaluronan Receptors
Bioassays and Physiological Analysis
Physical Sciences
Matrix Metalloproteinase 2
Anatomy
Statistics (Mathematics)
Research Article
Chemical Elements
medicine.medical_specialty
Normal diet
Renal cortex
Biology
Lithium
Research and Analysis Methods
03 medical and health sciences
Nephroblastoma Overexpressed Protein
Transforming Growth Factor beta2
Renal fibrosis
medicine
Genetics
Animals
RNA
Messenger
Rats
Wistar
Statistical Methods
Cytoplasmic Staining
Medulla
Renal Analysis
lcsh:R
Kidney metabolism
Biology and Life Sciences
Kidneys
Renal System
medicine.disease
Rats
030104 developmental biology
Specimen Preparation and Treatment
Multivariate Analysis
lcsh:Q
Mathematics
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 11, Iss 12, p e0168240 (2016)
ISSN: 1932-6203
Popis: Accurate diagnosis of fibrosis is of paramount clinical importance. A human fibrosis classifier based on metzincins and related genes (MARGS) was described previously. In this investigation, expression changes of MARGS genes were explored and evaluated to examine whether the MARGS-based algorithm has any diagnostic value in a rat model of lithium nephropathy. Male Wistar rats (n = 12) were divided into 2 groups (n = 6). One group was given a diet containing lithium (40 mmol/kg food for 7 days, followed by 60mmol/kg food for the rest of the experimental period), while a control group (n = 6) was fed a normal diet. After six months, animals were sacrificed and the renal cortex and medulla of both kidneys removed for analysis. Gene expression changes were analysed using 24 GeneChip® Affymetrix Rat Exon 1.0 ST arrays. Statistically relevant genes (p-value1.5, t-test) were further examined. Matrix metalloproteinase-2 (MMP2), CD44, and nephroblastoma overexpressed gene (NOV) were overexpressed in the medulla and cortex of lithium-fed rats compared to the control group. TGFβ2 was overrepresented in the cortex of lithium-fed animals 1.5-fold, and 1.3-fold in the medulla of the same animals. In Gene Set Enrichment Analysis (GSEA), both the medulla and cortex of lithium-fed animals showed an enrichment of the MARGS, TGFβ network, and extracellular matrix (ECM) gene sets, while the cortex expression signature was enriched in additional fibrosis-related-genes and the medulla was also enriched in immune response pathways. Importantly, the MARGS-based fibrosis classifier was able to classify all samples correctly. Immunohistochemistry and qPCR confirmed the up-regulation of NOV, CD44, and TGFβ2. The MARGS classifier represents a cross-organ and cross-species classifier of fibrotic conditions and may help to design a test to diagnose and to monitor fibrosis. The results also provide evidence for a common pathway in the pathogenesis of fibrosis.
Databáze: OpenAIRE
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