Volume 83, Issue 2, Pages 242-250 (February 2013) Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats  David P. Basile, Melinda R. Dwinell, Shur-Jen Wang, Brian D. Shames, Deborah L. Donohoe, Shaoying Chen, Rajasree Sreedharan, Scott K. Van Why  Kidney International  Volume 83, Issue 2, Pages 242-250 (February 2013) DOI: 10.1038/ki.2012.391 Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 1 Resistance to ischemia reperfusion (I/R)–induced acute kidney injury (AKI) in Brown Norway (BN) and SS-BN consomic rats. Except for SS sham, rats were subjected to 45min of bilateral renal ischemia with 24h reflow. Data are presented as mean±1s.d. of the serum creatinine values at 24h. The N for each group is indicated in individual bars; *indicates P<0.001 versus SS rats post I/R. Numbers on the x axis are the BN chromosome introgressed into the SS background (e.g., 7 is SS-7BN). Kidney International 2013 83, 242-250DOI: (10.1038/ki.2012.391) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 2 Representative renal histology of salt-sensitive (SS), Brown Norway (BN), and selected consomic rat strains 24h after ischemia reperfusion (I/R) injury. Photomicrographs are shown in the renal outer medulla for the (a) BN, (b) SS, (c) SS-1BN, (d) SS-4BN, (e) SS-7BN, and (f) SS-8BN. White arrows indicate periodic acid–Schiff-positive brush border staining, whereas areas of necrotic cellular debris are indicated by *. In some tubules, although cellular debris is present, dedifferentiated and viable cells are clearly seen (thick arrow). (g) The results of the quantitative analysis of the tubular injury scores for the renal cortex (open) or outer medulla (hashed bar). Data are expressed as percentage of affected tubules and are presented as mean±s.e. The N for each group is shown; *P<0.05 indicates significantly reduced versus SS rats; # indicates that injury in BN rats is less than that in the consomic-protected strains. Kidney International 2013 83, 242-250DOI: (10.1038/ki.2012.391) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 3 In silico analysis to identify potential candidate genes that confer protection against acute kidney injury (AKI). To generate a list of potential candidate genes that have a role in the resistance to ischemic injury found in the Brown Norway (BN) strain, an in silico analysis was performed to identify candidate genes involved in the resistance to ischemia reperfusion (I/R)–induced AKI. (a) Number of genes with annotations to three disease ontology (DO) terms (reperfusion injury, ischemia, and kidney disease) for the resistant chromosomes (consomics with a resistant phenotype). (b) Number of renal function quantitative trait loci (QTLs) located on chromosomes that protect against I/R injury. (c) Potential candidate genes were identified if the gene had DO annotations for reperfusion injury, ischemia, and kidney disease and was found within a renal function QTL. (d) Summary of candidate genes and the QTLs that overlap with the candidate genes. Chr, chromosome. Kidney International 2013 83, 242-250DOI: (10.1038/ki.2012.391) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 4 Illustrative map of renal quantitative trait loci (QTLs) and candidate genes associated with protection from acute kidney injury (AKI) in Brown Norway (BN) consomic strains. Genome Viewer (GViewer) output from the Rat Genome Database provides a complete genome view of the prioritized candidate genes (indicated in blue) and QTLs (indicated in red). These overlapping renal function QTLs were included in the final step of the in silico analysis, and candidate alleles were identified using disease ontology terms to narrow down the candidate gene list. Kidney International 2013 83, 242-250DOI: (10.1038/ki.2012.391) Copyright © 2013 International Society of Nephrology Terms and Conditions