1. Congenital DNA repair deficiency results in protection against renal ischemia reperfusion injury in mice.
- Author
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Susa D, Mitchell JR, Verweij M, van de Ven M, Roest H, van den Engel S, Bajema I, Mangundap K, Ijzermans JN, Hoeijmakers JH, and de Bruin RW
- Subjects
- Animals, Cockayne Syndrome genetics, Cockayne Syndrome metabolism, Cockayne Syndrome physiopathology, DNA Repair Enzymes genetics, Disease Models, Animal, Genetic Predisposition to Disease genetics, Glucose Tolerance Test, Immunity, Innate genetics, Insulin Resistance genetics, Ischemia physiopathology, Ischemia prevention & control, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Poly-ADP-Ribose Binding Proteins, Renal Insufficiency physiopathology, Renal Insufficiency prevention & control, Reperfusion Injury physiopathology, Reperfusion Injury prevention & control, DNA Repair genetics, Ischemia genetics, Renal Insufficiency genetics, Reperfusion Injury genetics, Stress, Physiological genetics
- 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.
- Published
- 2009
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