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

Abstract

BackgroundThe 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.MethodsSingle-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).ResultsAll 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.ConclusionsGeneration 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.

Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome

“…A recent report by Chung et al. 30 suggested that Synpo2 expression may be largely enhanced in smooth muscle cells rather than mesangial cells; however, our findings are consistent with most of the recently published single cell RNA sequencing data 7 ( http://humphreyslab.com/SingleCell ). Furthermore, we confirm that SYNPO2 co-localizes with F-actin and has F-actin bundling activity, and both mutant variants showed decreased actin bundling activity.…”

Integration of spatial and single-cell transcriptomics localizes epithelial cell–immune cross-talk in kidney injury

“…Single cell sequencing has rapidly enhanced our knowledge of the kidney's expression signature and its cell types (27), thereby helping to uncover the pathophysiology of a variety of conditions including early diabetic nephropathy (28), the composition of a Wilm's tumor (29), and allograft rejection (5). Similar studies in the mouse have facilitated query of murine disease state models (30) and the response to water deprivation (31). In addition, scRNAseq and snRNAseq are foundational technologies for the generation of a kidney cell atlas and detection of novel cell types in the human (2) and the mouse (4,32,33).…”

Single-Nucleus Transcriptomic Analysis Reveals Important Cell Cross-Talk in Diabetic Kidney Disease

“…Single-cell sequencing (scRNA-seq) is a technological evolution and provides unprecedented insight into cell communication (10)(11)(12). In experimental studies of renal diseases (13)(14)(15)(16), scRNA-seq technology furthers the understanding of the mechanisms and cell-to-cell interactions involved in disease pathogenesis. In human kidneys (17)(18)(19), scRNA-seq has helped to identify novel cell types, reveal potential mechanisms, and investigate cell communication from distinct aspects.…”