Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury

Studies suggest that biological sex influences susceptibility to kidney diseases with males demonstrating greater risk for developing ischemic acute injury (AKI). Sex-related differences in mitochondrial function and homeostasis exist, likely contributing sexual dimorphism injury, but the mechanisms are not well characterized. Our observations reveal lower baseline expression of Sirtuin-3 (Sirt3, a major acetyltransferase) kidneys male mice versus females. We tested hypothesis differential Sirt3 may mediate AKI using bilateral ischemia-reperfusion (IRI) model three transgenic mouse models: (1) global overexpression Sirt3; (2) inducible, tubule-specific knockdown (iKD); (3) knockout. Low (mtSirt3) females is associated development tubular epithelium vacuoles, increased ROS IRI. Transgenic protects against IRI vacuoles. In both sexes, partial epithelium-specific display intermediate - while knockout highest Female iKD demonstrate decreased survival after indistinguishable from control males, abolishing protective effects observed Mechanistically, mtSirt3 hormone-dependent; estradiol increases testosterone decreases protein. results an important contributor sex-related susceptibility, potential therapeutic target clinical management AKI.