title: Congenital DNA repair deficiency results in protection against renal ischemia reperfusion injury in mice.
abstract: Cockayne syndrome and other segmental progerias with inborn defects in DNA repair mechanisms are thought to be due in part to hypersensitivity to endogenous oxidative DNA damage. The accelerated aging-like symptoms of this disorder include dysmyelination within the central nervous system, progressive sensineuronal hearing loss and retinal degeneration. We tested the effects of congenital nucleotide excision DNA repair deficiency on acute oxidative stress sensitivity in vivo. Surprisingly, we found mouse models of Cockayne syndrome less susceptible than wild type animals to surgically induced renal ischemia reperfusion injury, a multifactorial injury mediated in part by oxidative damage. Renal failure-related mortality was significantly reduced in Csb(-/-) mice, kidney function was improved and proliferation was significantly higher in the regenerative phase following ischemic injury. Protection from ischemic damage correlated with improved baseline glucose tolerance and insulin sensitivity and a reduced inflammatory response following injury. Protection was further associated with genetic ablation of a different Cockayne syndrome-associated gene, Csa. Our data provide the first functional in vivo evidence that congenital DNA repair deficiency can induce protection from acute stress in at least one organ. This suggests that while specific types of unrepaired endogenous DNA damage may lead to detrimental effects in certain tissues, they may at the same time elicit beneficial adaptive changes in others and thus contribute to the tissue specificity of disease symptoms.
authors.affiliation: Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Denis
authors.initials: D
authors.lastname: Susa
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
authors.forename: Marielle
authors.initials: M
authors.lastname: Verweij
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Ven
authors.forename: Henk
authors.initials: H
authors.lastname: Roest
authors.forename: Sandra
authors.initials: S
authors.lastname: van den Engel
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Bajema
authors.forename: Kirsten
authors.initials: K
authors.lastname: Mangundap
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin