title: Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats.
abstract: Brown Norway rats (BN, BN/NHsdMcwi) are profoundly resistant to developing acute kidney injury (AKI) following ischemia reperfusion. To help define the genetic basis for this resistance, we used consomic rats, in which individual chromosomes from BN rats were placed into the genetic background of Dahl SS rats (SS, SS/JrHsdMcwi) to determine which chromosomes contain alleles contributing to protection from AKI. The parental strains had dramatically different sensitivity to ischemia reperfusion with plasma creatinine levels following 45 min of ischemia and 24 h reperfusion of 4.1 and 1.3 mg/dl in SS and BN, respectively. No consomic strain showed protection similar to the parental BN strain. Nine consomic strains (SS-7(BN), SS-X(BN), SS-8(BN), SS-4(BN), SS-15(BN), SS-3(BN), SS-10(BN), SS-6(BN), and SS-5(BN)) showed partial protection (plasma creatinine about 2.5-3.0 mg/dl), suggesting that multiple alleles contribute to the severity of AKI. In silico analysis was performed using disease ontology database terms and renal function quantitative trait loci from the Rat Genome Database on the BN chromosomes giving partial protection from AKI. This tactic identified at least 36 candidate genes, with several previously linked to the pathophysiology of AKI. Thus, natural variants of these alleles or yet-to-be identified alleles on these chromosomes provide protection against AKI. These alleles may be potential modulators of AKI in susceptible patient populations.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. dpbasile@iupui.edu
authors.forename: David P
authors.initials: DP
authors.lastname: Basile
authors.forename: Melinda R
authors.initials: MR
authors.lastname: Dwinell
authors.forename: Shur-Jen
authors.initials: SJ
authors.lastname: Wang
authors.forename: Brian D
authors.initials: BD
authors.lastname: Shames
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Donohoe
authors.forename: Shaoying
authors.initials: S
authors.lastname: Chen
authors.forename: Rajasree
authors.initials: R
authors.lastname: Sreedharan
authors.forename: Scott K
authors.initials: SK
authors.lastname: Van Why
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics*; D000818:Animals; D033481:Chromosomes, Mammalian / Q000502:physiology*; D003404:Creatinine / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D000076249:Heat Shock Transcription Factors; D040641:Quantitative Trait Loci; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D015427:Reperfusion Injury / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D003404:Creatinine