Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice

Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria in mice, is related to the single-nucleotide polymorphism (SNP) C6418T of the Prkdc gene encoding for the DNA-repair enzyme DNA-PKcs. In addition, plasminogen (Plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the Prkdc gene in C57BL/6 (Prkdc(C6418/C6418)) and 129S1/SvImJ (Prkdc(T6418/T6418)) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with Prkdc(T6418/T6418) developed proteinuria. Genetic deficiency of Plg (Plg(-/-)) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of Plg in Plg(+/+) mice after doxorubicin injection involving histone H2B as Plg receptor. In doxorubicin-resistant C57BL/6 mice, Plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two-hit process requiring the C6418T SNP in the Prkdc gene and subsequent glomerular binding of Plg.

Automated summary

In susceptibility to doxorubicin-induced nephropathy, the interaction between the C6418T SNP in the Prkdc gene and Plg plays a crucial role, following a hierarchical two-hit process in 129S1/SvImJ mice.