2026/06/15 by Weiyuan Gong, Sisi Yang, Yujia Wang +7
Biochemistry, Genetics and Molecular Biology · Medicine · Neuroscience · #Inflammasome and immune disorders #Sirtuins and Resveratrol in Medicine #Tryptophan and brain disorders
paper · doi:10.1681/asn.0000001149
openalex publication_date 2026/06/15 · openalex created_date 2026/06/16 · openalex updated_date 2026/07/31
KEY POINTS: Susceptibility to ischemia-reperfusion-induced AKI was sexually dimorphic and associated with sex difference in KYNU expression and de novo NAD + flux. Androgen-dependent deficiency in kynureninase expression impaired NAD +de novo synthesis under stress, contributing to male mice susceptibility to kidney injury. Kynureninase deletion in female mice abrogated protection against ischemia‑reperfusion injury, which was rescued by nicotinamide mononucleotide treatment. BACKGROUND: Biological sex is recognized as a modulator of AKI, whereas the underlying molecular mechanisms remain incompletely understood. METHODS: An ischemia-reperfusion injury-induced AKI model was established on adult male and female wild-type and female kynureninase ( Kynu ) knockout ( Kynu-/- ) mice. Prepubertal wild-type mice were gonadectomized and euthanized 5 weeks later. 13 C-tryptophan was administered by tail vein injection, and renal levels of NAD + and metabolites in the de novo pathway were examined using high-performance liquid chromatography. Quinolinic acid (QA) and nicotinamide mononucleotide were administered by oral gavage or intraperitoneal injection. RESULTS: Male mice were more susceptible to ischemic kidney injury, accompanied by a more pronounced decrease in NAD + levels compared with female mice. Further experiments demonstrated that the expression of KYNU, a central enzyme in the de novo NAD + biosynthetic pathway, was significantly downregulated in male kidneys. High-performance liquid chromatography analysis revealed that male mice exhibited significantly lower renal QA (a downstream metabolite of KYNU) and reduced tryptophan-derived NAD + after ischemia-reperfusion injury compared with females, reflecting impaired NAD +de novo biosynthesis. Notably, QA supplementation effectively alleviated the exacerbated kidney injury observed in male mice. In addition, castration markedly elevated renal Kynu expression to levels comparable with those in females, which decreased again after testosterone supplementation. Furthermore, genetic ablation of Kynu replicated the decreased renal QA and NAD + levels observed in male mice, accompanied by exacerbated kidney damage. Supplementation with nicotinamide mononucleotide, an NAD + precursor, significantly alleviated AKI in Kynu-/- mice. CONCLUSIONS: Androgen-dependent KYNU downregulation was found in the adult mouse kidney. Disrupted NAD +de novo biosynthesis caused by Kynu deficiency mediated the sex-biased susceptibility to AKI.