Resistance to doxorubicin-induced proteinuria and proteolytic activation of ENaC in 129S2/SvPas mice.

Doxorubicin treatment of mice represents a convenient model to study the effects of proteinuria on proteolytic processing of the epithelial Na+ channel (ENaC) and urinary Na+ and fluid handling. Prior studies have shown enhanced ENaC γ subunit proteolysis and Na+ and fluid retention in 129S1/SvImJ mice treated with doxorubicin. We examined whether 129S2/SvPas mice could be used to study doxorubicin-induced proteinuria. 129S2/SvPas mice treated with 18 μg/g doxorubicin exhibited significantly reduced urinary albumin/creatinine compared to that described for 129S1/SvImJ mice. Proteolytic processing of ENaC's γ subunit and sensitivity of urinary Na+ and K+ to the ENaC blocker, benzamil, were not enhanced by doxorubicin. Differences in the DNA repair enzyme, DNA-activated protein kinase (DNA-PKcs) may contribute to the difference in doxorubicin susceptibility of 129S2/SvPas and 129S1/SvImJ mice. Sequencing of the Prkdc, encoding DNA-PKcs, showed that 129S2/SvPas mice lack a polymorphism (Arg2140Cys) that has previously been implicated in doxorubicin sensitivity in 129S1/SvImJ mice. The status of this polymorphism in various experimental mouse strains, and therefore implications for studying doxorubicin-induced proteinuria, is discussed.