Sex-Specific Differences in Rat Renal CYP Enzyme Expression and Activity Following Isoproterenol-Induced Injury.

BACKGROUND AND

OBJECTIVE

The expression and activity of cytochrome P450 (CYP) enzymes are influenced by sex differences, and their arachidonic acid (AA)-mediated metabolites play crucial roles in physiological and pathological conditions. Isoproterenol (ISO) can induce kidney injury mediated by the activation of the renin-angiotensin-aldosterone system and may progress to end-stage renal disease. Our study aims to investigate the sex-related differences in CYP enzymes following ISO-induced kidney injury.

METHODS

Male and female rats were injected with ISO (1 mg/kg, i.p.) for 7 days. Kidney tissues were analyzed for injury markers, and the gene and protein expression of CYP enzymes were measured using real-time PCR and Western blot, respectively. Kidney microsomes were incubated with AA, and the formation rate of the metabolites was analyzed. The level of microsomal epoxide hydrolase (mEH) was evaluated.

RESULTS

Our results indicated that ISO-treated female rats exhibited an increase in the kidney injury markers. Gene expression of CYP1A1, CYP4A1, CYP4F1, and CYP2B was significantly elevated in ISO-treated female kidneys. In treated males, CYP4F6 increased markedly while CYP2C11 decreased significantly. The protein levels of CYP4A and CYP2E1 increased in both sexes, while CYP1B1 increased only in male treated rats. The formation rate of 14S(15R) and 5S(6R) epoxyeicosatrienoic acids significantly decreased in treated females, likely due to having higher levels of mEH.

CONCLUSION

Our findings revealed significant sex differences in kidney injury severity and CYP expression, with female rats experiencing more pronounced renal injury. These results highlight the potential relationship between kidney injury progression and CYP enzyme levels and activity, which may have implications for sex-specific therapeutic strategies.