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Abstract: TH-PO139

Kynu Mediated Sex Dimorphism of AKI Through an NAD+ Dependent Manner

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gong, Weiyuan, Fudan University, Shanghai, Shanghai, China
  • Hao, Chuanming, Fudan University, Shanghai, Shanghai, China
Background

AKI is a disorder that is associated with high mortality and a high risk for development of CKD. It is well documented that female gender is associated with enhanced tolerance to kidney injury, the underlying mechanism is incompletely understood. Mounting evidence suggests that NAD+ levels are associated with kidney tolerance to injury. The present study examined NAD+ synthetic pathways and their association with gender related susceptibility to AKI.

Methods

IRI induced AKI was performed at 8-week-old C57BL/6J mice, bilateral renal pedicles were clamped for 22min(26min for 12-week-old female KYNU-/- and wt mice). The animals were euthanized 48 hours later. Prepubertal female/male mice were ovariectomized or castrated respectively, and euthanized after 5 weeks. The enzymes expression was examined using Immunoblot, qPCR. The metabolites of NAD+de novo pathway were examined using HPLC.

Results

Following IRI, male mice exhibited severe renal injury compared to female mice, manifested as higher BUN and Scr levels. Further investigation revealed that male kidney express lower levels of kynureninase (KYNU), one of the enzymes of the NAD+ de novo pathway, at adult age and prepubertal castration significantly increase renal Kynu expression but not ovariectomy, demonstrating that the expression of KYNU is regulated by testosterone but not estrogen.
We next measured the metabolites concentration in kidney and urine. Result showed no difference in the metabolite under physiological condition, however, with the insult of IRI, we observed elevated levels of intermediate metabolites and NAD+ in female kidney compare to male, suggesting the NAD+ de novo pathway was more activated in the female kidney, which may contribute to the NAD+ synthesis and improve AKI.
Thus, we generated KYNU knockout mice and found that genetic ablation of KYNU significantly decreased urinary and kidney metabolites and inhibited the NAD+ de novo synthetic pathway, accompanied by sharpening kidney damage compared to wt mice following IRI, while supplementation with nicotinamide mononucleotide (NMN), an NAD+ precursor, restored NAD+ levels and significantly alleviated kidney injury in KYNU-/- mice.

Conclusion

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

Funding

  • Government Support – Non-U.S.