Actinonin, a meprin inhibitor, protects ischemic acute kidney injury in male but not in female rats

We investigated the effects of actinonin, an inhibitor of a matrix-degrading enzyme meprin, on ischemic acute kidney injury in male and female rats, and these were compared with the effects of verapamil, a Ca2+ channel blocker. Ischemic acute kidney injury was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function and histology of both males and females showed significant deterioration. The degrees of renal dysfunction and histological damage were much more severe in males than in females. Pre-ischemic treatment with actinonin (10 or 30 mg/kg, i.v.) dose-dependently attenuated the ischemia/reperfusion-induced renal injury in male rats, but failed to improve the renal injury in female rats. On the other hand, verapamil (1 mg/kg, i.v.) could efficiently prevent the ischemic acute kidney injury in female rats, as well as male rats. These results indicate that the renoprotective effect of actinonin is male-specific, thereby suggesting that meprin is involved in exacerbation of ischemia/reperfusion-induced renal injury in male rats. The possibility that meprin is a key factor involved in the sex difference in the pathogenesis of ischemic acute kidney injury, warrants further attention.