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

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)242-250
Number of pages9
JournalKidney international
Volume83
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • acute kidney injury
  • genetic susceptibility
  • ischemia reperfusion

ASJC Scopus subject areas

  • Nephrology

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    Basile, D. P., Dwinell, M. R., Wang, S. J., Shames, B. D., Donohoe, D. L., Chen, S., Sreedharan, R., & Van Why, S. K. (2013). Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats. Kidney international, 83(2), 242-250. https://doi.org/10.1038/ki.2012.391