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Kidney Week

Abstract: PO0329

The Role of KYNU in Mediating Sex Dimorphism of AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gong, Weiyuan, Fudan University, Shanghai, Shanghai, China
  • Hao, Chuan-Ming, Fudan University, Shanghai, Shanghai, China
Background

Acute kidney injury (AKI) is a disorder that is associated with high mortality and a high risk for development of chronic kidney disease. It is well documented that female gender is associated with relative resistance to kidney injury, the underlying mechanism is incompletely understood. Mounting evidence suggests that NAD+ levels are associated with enhanced tolerance of kidney to injury, and exogenous supplement of NAD+ precursor NMN alleviate AKI. The present study examined NAD+ synthesis pathways and their association with gender related susceptibility to AKI.

Methods

IRI AKI model was performed on 8 weeks old wild-type C57BL/6J female and male mice, bilateral renal pedicles were clamped for 22 minutes. The animals were euthanized 48 hours after reperfusion. Prepubertal (3 weeks old) wild-type C57BL/6J female or male mice were ovariectomized or castrated respectively and were euthanized after 5 weeks for renal KYNU expression analysis. The metabolites of NAD+ de novo pathway were examined by HPLC.

Results

Following IRI, female mice had less severe kidney injury, manifested as lower BUN and Cr levels, lower kidney injury marker (NGAL) expression and alleviated tubule damage.
Further study revealed renal KYNU, but not other enzymes involved in the NAD+ synthesis pathways, was 5 fold higher in female mice compared to male at age 8 weeks, despite that it is comparable between female and male mice at age 7 days. Prepubertal oophorectomy in female mice did not significantly decrease renal KYNU expression, in contrast, prepubertal castration of male mice increased renal KYNU levels to that seen in female, demonstrating KYNU is regulated by testosterone other than estrogen.
HPLC result showed no difference in the metabolites concentration between male and female mice under physiological condition, however, following IRI, 3-HAA and QA concentration, which are precursors for NAD+, were significantly upregulated in the female urine but remained unchanged in the male urine, so as QA concentration in the female kidney, suggesting kynurenine pathway is more activated in the female kidney under AKI condition, which may contribute to NAD+ synthesis and improve AKI.

Conclusion

We propose a KYNU-dependent mechanism, which contributes to the relative renoprotection of female after IRI by regulating renal NAD+ level. NAD+ de novo synthesis pathway may be a potential target for IRI-AKI treatment.

Funding

  • Government Support – Non-U.S.