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Abstract: PO1676

SIRT3 Confers Protection and Mediates Sex Differences in Aging-Related Kidney Injury

Session Information

Category: Geriatric Nephrology

  • 1100 Geriatric Nephrology

Authors

  • Shen, Huiyun, Baylor College of Medicine Department of Medicine - Nephrology, Houston, Texas, United States
  • Holliday, Michael, Baylor College of Medicine Department of Medicine - Nephrology, Houston, Texas, United States
  • Li, Qingtian, Baylor College of Medicine Department of Medicine - Nephrology, Houston, Texas, United States
  • Tan, Li, Baylor College of Medicine Department of Medicine - Nephrology, Houston, Texas, United States
  • Sheikh-Hamad, David, Baylor College of Medicine Department of Medicine - Nephrology, Houston, Texas, United States
  • Pan, Jenny S., Baylor College of Medicine Department of Medicine - Nephrology, Houston, Texas, United States
Background

Fibrosis and mitochondrial dysfunction are hallmarks of most progressive CKD. Studies suggest women have slower progression of CKD and lower ESKD incidence before menopause vs. men. SIRT3, a major mitochondrial acetyltransferase, is critical in maintaining mitochondrial homeostasis and anti-oxidative defense. We observe higher kidney mitochondrial SIRT3 (mtSIRT3) in females vs. males; mtSIRT3 declines with age but sex differences persist. We hypothesize that SIRT3 protects from and mediates sex differences in aging-related kidney injury and fibrosis.

Methods

Male and female WT, SIRT3 transgenic (Tg), inducible kidney tubule-specific SIRT3 knockout (iKO) or global SIRT3 KO mice were aged under physiologic conditions. Kidney fibrosis was detected by trichrome staining and expression of fibrosis markers (α-SMA; fibronectin). 6-month (mo) old male or female WT mice were treated with S.C. implantation of a 200 mg, 21-day-release testosterone pellet for 3 wks.

Results

In male mice, we observed that lower kidney mtSIRT3 expression vs. age-matched females is associated with higher baseline ROS generation, and development of tubular cytoplasmic vacuoles by 6-mo and fibrosis by 14-mo. Aging-related changes are attenuated in SIRT3 Tg males. Conversely, 6-mo iKO male mice display higher ROS, tubular injury and fibrosis vs. age-matched control males. In contrast to male mice, WT females display minimal tubular vacuolization or fibrosis at 14-mo. SIRT3 knockdown aggravates tubular injury and fibrosis in aged 14-mo iKO females; outcomes similar to WT males. Furthermore, young (2-3 mo) male and female global SIRT3 KO mice display baseline kidney injury characterized by: increased urinary albumin excretion, ROS and tubular injury vs. WT. Mechanistic studies show that testosterone (T) administration to WT males increased serum T ~4-fold, decreased kidney mtSIRT3, and caused kidney injury (decreased CrCl and increased tubular vacuolization). T increased kidney mtSIRT3 and caused no measurable kidney injury in WT females, possibly due to an associated increase in serum estradiol.

Conclusion

1) SIRT3 is critical for kidney tubular epithelial cell survival under physiologic conditions, and inhibits development of tubular injury and fibrosis in aged kidneys; 2) sex-dependent differences in kidney SIRT3 expression may mediate sexual dimorphism in CKD outcomes.

Funding

  • Veterans Affairs Support