A Landscape of Genetic and Cellular Hallmarks in Chronic Kidney Disease

Chronic kidney disease (CKD) affects >800 million individuals worldwide, while spatiotemporal inventory of CKD hallmarks is lacking. Here, we comprehensively map the landscape of 18,740 genes, 24,604 genesets, and 19 cell types in a mouse CKD model, using spatial RNA sequencing and in vivo two-photon imaging. Unsupervised transcriptome clustering identifies seven spatially distinguished clusters, which exhibit systemic transcriptome activation in CKD. Comparative pathway analysis across-kidney regions and CKD progression reveals novel genetic hallmarks, such as rapid metabolic reduction, early increase of intracellular stress, chronic inflammation, interstitial angiogenesis and fibrosis. Single-cell deconvolution analysis unravels kidney-wide cellular remodeling, including endothelial cell (EC) and proximal tubule cell loss, immune cell infiltration, and fibroblast activation. Using two-photon imaging, we luminate the progression and interaction between EC and tubule dysfunction, macrophages infiltration, and fibroblast activation in mice CKD kidneys. Furthermore, our comparative genetic analysis shed light on the CKD genetic translatability between mice and human.