Spatial characterization of sex differential regulations in kidney across lifespan

There is a clear sex bias in the incident rates and progressions of many kidney diseases and kidney cancers. To better understand the genetic and epigenetic regulation of kidney sexual dimorphism, we integrated data from 6 platforms, namely single nucleus sequencing (snRNA-Seq and snATAC-Seq), spatial transcriptomics (Visium and Xenium), and protein imaging (CODEX & IF) to build a spatially resolved molecular atlas for the mouse kidney of both sexes throughout the lifespan, from embryo to old age. We demonstrate that proximal tubules (PT) have the most sex-biased differentially expressed genes (DEGs), which appear after 3 weeks of age and are associated with hormonal regulations. We reveal the potential mechanism of direct and indirect involvement of androgen and estrogen, respectively, in sex-biased gene expression regulations in the kidney. Moreover, older male mice exhibit more aging-related gene alterations in loops of Henle and PTs, while older females show more aging-related gene alterations in fibroblasts. Our results furnish the community with rich resources and an enhanced understanding of spatially resolved gene expression and hormone regulation for sexual dimorphism in the kidney across the lifespan.多种肾脏疾病与肾癌的发病率及进展均存在显著的性别偏倚。为深入解析肾脏性别二态性（sexual dimorphism）的遗传与表观遗传调控机制，本研究整合了6类平台的数据，分别为单细胞核测序（single nucleus sequencing，涵盖snRNA-Seq与snATAC-Seq）、空间转录组学（spatial transcriptomics，涵盖Visium与Xenium平台）以及蛋白质成像（protein imaging，涵盖CODEX与免疫荧光immunofluorescence，IF），构建了覆盖从胚胎期至老年阶段的两性小鼠肾脏空间分辨分子图谱。我们证实近端小管（proximal tubules，PT）携带有最多的性别偏倚差异表达基因（differentially expressed genes，DEGs），此类基因于小鼠3周龄后开始表达，且与激素调控密切相关。本研究揭示了雄激素与雌激素分别通过直接与间接途径参与肾脏性别偏倚基因表达调控的潜在机制。此外，老年雄性小鼠的亨利袢（loops of Henle）与近端小管中存在更多衰老相关基因表达改变，而老年雌性小鼠的成纤维细胞（fibroblasts）中则呈现更为显著的此类改变。本研究为领域内提供了丰富的研究资源，同时深化了学界对全生命周期内肾脏性别二态性的空间分辨基因表达与激素调控机制的理解。