Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury

Significance Statement Single-cell transcriptomics techniques have revolutionized the ability to characterize cells from heterogeneous organs like the kidney. Although glomerular disorders are an important cause of CKD, a thorough characterization of the cells in the glomerulus has remained challenging due to the technical difficulties of isolating undamaged cells, especially from glomeruli of diseased animals. This study provides a comprehensive single-cell atlas, based on approximately 75,000 cells, from glomeruli of healthy mice and mice injured in four ways, including all cell types present. The data set will be a valuable resource for generating precise tools to interrogate specific glomerular cell types and in identifying genes involved in the pathogenesis of glomerular diseases. Background The glomerulus is a specialized capillary bed that is involved in urine production and BP control. Glomerular injury is a major cause of CKD, which is epidemic and without therapeutic options. Single-cell transcriptomics has radically improved our ability to characterize complex organs, such as the kidney. Cells of the glomerulus, however, have been largely underrepresented in previous single-cell kidney studies due to their paucity and intractability. Methods Single-cell RNA sequencing comprehensively characterized the types of cells in the glomerulus from healthy mice and from four different disease models (nephrotoxic serum nephritis, diabetes, doxorubicin toxicity, and CD2AP deficiency). Results All cell types in the glomerulus were identified using unsupervised clustering analysis. Novel marker genes and gene signatures of mesangial cells, vascular smooth muscle cells of the afferent and efferent arterioles, parietal epithelial cells, and three types of endothelial cells were identified. Analysis of the disease models revealed cell type–specific and injury type–specific responses in the glomerulus, including acute activation of the Hippo pathway in podocytes after nephrotoxic immune injury. Conditional deletion of YAP or TAZ resulted in more severe and prolonged proteinuria in response to injury, as well as worse glomerulosclerosis. Conclusions Generation of comprehensive high-resolution, single-cell transcriptomic profiles of the glomerulus from healthy and injured mice provides resources to identify novel disease-related genes and pathways.