Single-Cell Transcriptional Landscape of the Kidney Filter in Health and Disease

Abstract

Progressive chronic kidney diseases (CKDs) affect more than 700 million people worldwide and are increasing in prevalence. However, the sequence of events resulting in CKD progression remain poorly understood. Animal models of CKD exploring these issues are confounded by systemic toxicities or surgical interventions to acutely induce kidney injury. Loss of podocytes, specialized postmitotic cells lining the kidney filter (glomerulus), causes severe nephrotic syndrome, a type of CKD. We generated a novel CKD mouse model through the doxycycline-inducible podocyte-specific ablation of an essential endogenous molecule, CTCF, which leads to rapid podocyte loss (iCTCFpod-/-). iCTCFpod-/- mice develop all the hallmarks of CKD and die within 8–10 weeks from kidney failure. Dissection of the timeline leading to glomerular pathology in this CKD model led to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD in the absence of interstitial fibrosis. We sought to elucidate the mechanism by which podocyte ablation leads to kidney filter destruction and kidney failure. To identify the earliest transcriptional effects of podocyte ablation, in a cell type-specific manner, we performed single-cell RNA sequencing in iCTCFpod-/- mice after 1 week of doxycycline induction. Gene set enrichment analysis revealed that podocyte loss is mediated by disruption of focal adhesions and interactions with the glomerular basement membrane. Further, ligand-receptor interactions and circuits, that likely represent the first steps in disease initiation were identified. This work aligns with recent GWAS findings and points to potential therapeutic targets for the treatment of CKD.