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

Authors: SHEN, HUIYUN - Baylor College Of Medicine; HOLLIDAY, MICHAEL - Baylor College Of Medicine; SHEIKH-HAMAD, DAVID - Baylor College Of Medicine; LI, QINGTIAN - Baylor College Of Medicine; TONG, QIANG - Children'S Nutrition Research Center (CNRC); DAVID HAMAD, CHRISTOPHER - Baylor College Of Medicine; PAN, JENNY - Baylor College Of Medicine

Submitted to: Translational Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/20/2021
Publication Date: 3/28/2021
Citation: Shen, H., Holliday, M., Sheikh-Hamad, D., Li, Q., Tong, Q., David Hamad, C., Pan, J.S. 2021. Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury. Translational Research. https://doi.org/10.1016/j.trsl.2021.03.015.
DOI: https://doi.org/10.1016/j.trsl.2021.03.015

Interpretive Summary: Studies suggest that biological sex influences susceptibility to kidney diseases with males demonstrating greater risk for developing acute kidney injury. But the mechanisms are not well characterized. Our observations reveal lower baseline expression of Sirtuin-3 (Sirt3, an enzyme in the cellular powerhouse mitochondria) in the kidneys of male mice versus females. We tested the theory that differential expression of kidney Sirt3 may mediate sexual difference in kidney injury using a kidney injury model by blocking and then reopening blood vessels to kidney in three genetically engineered mouse models: (1) mice with ubiquitous overexpression of Sirt3; (2) mice with inducible, kidney-specific Sirt3 suppression; and (3) mice with whole body Sirt3 deletion. Low mitochondrial Sirt3 in males is associated with development of kidney defect and susceptibility to kidney injury. Overexpression of Sirt3 in males protects against kidney injury. In both sexes, mice with partial kidney-specific Sirt3 suppression display intermediate - while complete whole body Sirt3 deletion mice display the highest susceptibility to kidney injury. Inhibiting Sirt3 in the kidney of female mice resulted in decreased survival and kidney function after kidney injury, abolishing the protective effects observed in females. Furthermore, we found female sex hormone estrogen increases - while male hormone testosterone decreases Sirt3 protein. Our results demonstrate that Sirt3 is an important contributor to the observed sex-related differences in kidney injury susceptibility, and a potential therapeutic target in the clinical management of kidney injury.

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