Acute kidney injury (AKI) is a leading cause of morbidity and mortality. For decades, clinical observations and epidemiological studies have indicated that premenopausal women are less prone to AKI than men and postmenopausal women [1, 2]. However, the biological basis for this sex bias has remained largely unknown. In a recent Nature paper [3], Tonnus et al. provide a compelling mechanistic explanation, demonstrating that female renal tubules are inherently resistant to ferroptosis—a predominant mode of cell death involved in ischemic AKI—through oestradiol-mediated protection against this cell death.
AKI often arises from acute tubular necrosis, a pathological condition characterized by spatially propagating cell death along the nephron; this propagation has been shown to be driven, at least in part, by ferroptosis, a form of lipid peroxidation–driven cell death exacerbated by iron overload and impaired antioxidant defenses [4, 5]. Notably, previous studies reported that female mice were substantially more resistant to AKI and renal tubular ferroptosis propagation than male counterparts [6]. Using ischemia–reperfusion injury (IRI) models and ex vivo assays with isolated renal tubules, Tonnus et al. confirmed these findings and showed that ferroptotic cell death waves were prominent in male tubules but virtually absent in females; furthermore, while ferroptosis inhibitors have shown a robust protective effect in male mice, their benefit in females has been modest [3]. This resistance could not be explained by differences in the expression of classical ferroptosis regulators such as glutathione peroxidase 4 (GPX4).
The mouse zinc finger genes Zfy1 and Zfy2 are essential for male fertility. Recently, we produced Zfy1 knock-out (KO), Zfy2 KO, and Zfy1/2 double-knock-out (Zfy DKO) mice, and found that Zfy DKO males were infertile. The mechanism by which ZFY contributes to reproduction remains unknown but based on predicted protein sequence and in vitro assays we hypothesize that it controls expression of genes essential for spermatogenesis. To identify which genes ZFY regulates, we performed comparative transcriptome analysis of sorted male germ cells at three different spermatogenesis stages from three Zfy KO models and control wild-type males. Significantly altered germ cell transcriptomes were identified with Zfy2 KO and Zfy DKO. Analyses of differentially expressed genes supported that Zfy loss altered spermatogenesis, DNA packaging/chromatin organization, and apoptosis pathways. Alternative splicing was deregulated in Zfy KO models, affecting sperm function and chromatin regulation pathways. In support of in-silico findings, Zfy DKO males were shown to have impaired post-meiotic chromatin remodeling and sperm chromatin organization, functional sperm deficiencies, and increased germ cell apoptosis. ZFY regulation of apoptotic pathways was demonstrated also in transfected human cells. We conclude that Zfy is a critical regulator of meiosis and spermiogenesis in addition to its previously described function as a cell-cycle regulator.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：