Identification of nephropathy candidate genes by comparing sclerosis-prone and sclerosis-resistant mouse strain kidney transcriptomes

• Main Authors: El-Meanawy Ashraf, Schelling Jeffery R, Iyengar Sudha K, Hayden Patrick, Barathan Shrinath, Goddard Katrina, Pozuelo Fatima, Elashi Essam, Nair Viji, Kretzler Matthias, Sedor John R
• Format: Article
• Language: English
• Published: BMC 2012-07-01
• Series: BMC Nephrology
• Online Access: http://www.biomedcentral.com/1471-2369/13/61

<p>Abstract</p> <p>Background</p> <p>The genetic architecture responsible for chronic kidney disease (CKD) remains incompletely described. The Oligosyndactyly (<it>Os</it>) mouse models focal and segmental glomerulosclerosis (FSGS), which is associated with reduced nephron number caused by the <it>Os</it> mutation. The <it>Os</it> mutation leads to FSGS in multiple strains including the ROP-<it>Os</it>/+. However, on the C57Bl/6J background the mutation does not cause FSGS, although nephron number in these mice are equivalent to those in ROP-<it>Os</it>/+ mice. We exploited this phenotypic variation to identify genes that potentially contribute to glomerulosclerosis.</p> <p>Methods</p> <p>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-<it>Os</it>/+ and sclerosis resistant C57-<it>Os</it>/+ 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.</p> <p>Results</p> <p>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 (<it>Nrp2</it>), glutathione-S-transferase theta (<it>Gstt</it>1) and itchy (<it>Itch</it>). Of 34 genes with the most robust statistical difference in expression levels between ROP-<it>Os/</it>+ and C57-<it>Os/+</it> 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-<it>Os/</it>+ kidneys despite similar expression of the TGFβ ligand between the tested strains.</p> <p>Conclusions</p> <p>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.</p>