Identification of nephropathy candidate genes by comparing sclerosis-prone and sclerosis-resistant mouse strain kidney transcriptomes. BMC Nephrol 2012 Jul 19;13:61
Date
07/21/2012Pubmed ID
22813067Pubmed Central ID
PMC3502501DOI
10.1186/1471-2369-13-61Scopus ID
2-s2.0-84869763097 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
BACKGROUND: The genetic architecture responsible for chronic kidney disease (CKD) remains incompletely described. The Oligosyndactyly (Os) mouse models focal and segmental glomerulosclerosis (FSGS), which is associated with reduced nephron number caused by the Os mutation. The Os mutation leads to FSGS in multiple strains including the ROP-Os/+. However, on the C57Bl/6J background the mutation does not cause FSGS, although nephron number in these mice are equivalent to those in ROP-Os/+ mice. We exploited this phenotypic variation to identify genes that potentially contribute to glomerulosclerosis.
METHODS: To identify such novel genes, which regulate susceptibility or resistance to renal disease progression, we generated and compared the renal transcriptomes using serial analysis of gene expression (SAGE) from the sclerosis-prone ROP-Os/+ and sclerosis resistant C57-Os/+ mouse kidneys. We confirmed the validity of the differential gene expression using multiple approaches. We also used an Ingenuity Pathway Analysis engine to assemble differentially regulated molecular networks. Cell culture techniques were employed to confirm functional relevance of selected genes.
RESULTS: A comparative analysis of the kidney transcriptomes revealed multiple genes, with expression levels that were statistically different. These novel, candidate, renal disease susceptibility/resistance genes included neuropilin2 (Nrp2), glutathione-S-transferase theta (Gstt1) and itchy (Itch). Of 34 genes with the most robust statistical difference in expression levels between ROP-Os/+ and C57-Os/+ mice, 13 and 3 transcripts localized to glomerular and tubulointerstitial compartments, respectively, from micro-dissected human FSGS biopsies. Network analysis of all significantly differentially expressed genes identified 13 connectivity networks. The most highly scored network highlighted the roles for oxidative stress and mitochondrial dysfunction pathways. Functional analyses of these networks provided evidence for activation of transforming growth factor beta (TGFβ) signaling in ROP-Os/+ kidneys despite similar expression of the TGFβ ligand between the tested strains.
CONCLUSIONS: These data demonstrate the complex dysregulation of normal cellular functions in this animal model of FSGS and suggest that therapies directed at multiple levels will be needed to effectively treat human kidney diseases.
Author List
El-Meanawy A, Schelling JR, Iyengar SK, Hayden P, Barathan S, Goddard K, Pozuelo F, Elashi E, Nair V, Kretzler M, Sedor JRAuthor
Ashraf El-Meanawy MD, PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBiomarkers
Disease Resistance
Genetic Predisposition to Disease
Glomerulosclerosis, Focal Segmental
Kidney
Mice
Mice, Inbred C57BL
Mice, Transgenic
Sclerosis
Transcription Factors
Transcriptome
