Sex Dimorphism of NAD+De Novo Biosynthesis Mediates Sex-Biased Susceptibility to Ischemia-Reperfusion-Induced Acute Kidney Injury.

Abstract

Biological sex is recognized as a modulator of acute kidney injury (AKI), whereas the underlying molecular mechanisms remain incompletely understood. 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. 13C-tryptophan was administered via tail vein injection and renal levels of nicotinamide adenine dinucleotide (NAD+) and metabolites in the de novo pathway was examined using high-performance liquid chromatography (HPLC). Quinolinic acid (QA) and nicotinamide mononucleotide (NMN) were administered via oral gavage or intraperitoneal injection. Male mice were more susceptible to ischemic kidney injury, accompanied by a more pronounced decrease in NAD+ levels compared to 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. HPLC 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 to 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 to 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 NMN, an NAD+ precursor, significantly alleviated AKI in Kynu-/- mice. 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.