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.