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Kidney Week

Abstract: TH-PO104

Sex-Specific Regulation of Sirtuin-3 Mediates Differences in Ischemia-Reperfusion Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Pan, Jenny S., Michael E. DeBakey VAMC, Houston, Texas, United States
  • Yu, Chengtai, Baylor College of Medicine, Houston, Texas, United States
  • Li, Qingtian, Baylor College of Medicine, Houston, Texas, United States
  • Sheikh-Hamad, David, Baylor College of Medicine, Houston, Texas, United States
Background

Sex influences susceptibility to kidney ischemia-reperfusion injury (IRI), and sex hormones play a crucial role. We previously showed that a pathway from stanniocalcin-1 (STC1) mediated AMPK activation to induction of mitochondrial sirtuin-3 (mtSIRT3) suppresses ROS and confers resistance to kidney IRI. Current observations reveal increased baseline kidney expression of STC1 and SIRT3, and AMPK activation in female vs male mice. We hypothesized that SIRT3 mediates sex differences in response to IRI.

Methods

Male and female wild-type (WT) or SIRT3 transgenic (Tg) mice were subjected to bilateral kidney IR (clamping of renal pedicles for 30 min). Male or female WT mice were treated with testosterone for 2 weeks (s.c. implantation of 21-day release, 200mg pellet). HEK cells were treated with 17β-estradiol, testosterone or vehicle.

Results

pAMPK and mtSIRT3 expression are higher in kidneys of WT female mice vs. males; pAMPK and SIRT3 decline with age but sex differences persist. At age 6 months, male WT kidneys display tubular vacuolization, which is absent in male SIRT3Tg mice. Male SIRT3Tg mice demonstrate resistance to IR [preserved creatinine clearance (CrCl) and morphology; less ROS] and better survival vs WT males; outcomes similar to WT females. In WT females, kidney mtSIRT3 expression correlates positively with plasma estradiol and negatively with testosterone levels. In WT males, kidney mtSIRT3 only correlates negatively with plasma testosterone. Testosterone administration to 6 months-old WT males causes kidney injury (decreased CrCl; increased tubular vacuolization), and decreases kidney mtSIRT3 expression with no effect on whole cell SIRT3. Testosterone administration to WT females increases whole cell- and mtSIRT3 (maybe due to associated rise in plasma estradiol) and causes no measurable kidney injury. In HEK cells, estradiol dose-dependently increases SIRT3 mRNA, whole cell- and mtSIRT3 protein, and ERβ and ERRα mRNA. Testosterone dose-dependently decreases mtSIRT3 protein expression with no effect on whole cell SIRT3 protein or SIRT3 mRNA.

Conclusion

The data suggest: 1) SIRT3 ameliorates kidney IRI; 2) decreased SIRT3 expression underlies increased susceptibility to ischemic injury in male mice; 3) sex steroids regulate mtSIRT3 expression, estrogen via transcriptional regulation and testosterone via reduced mitochondrial targeting.

Funding

  • Veterans Affairs Support