Single-Cell Transcriptomics Reveal Disrupted Kidney Filter Cell-Cell Interactions after Early and Selective Podocyte Injury

Abbe R. Clark, Jamie Marshall, Yiming Zhou, Monica S. Montesinos, Haiqi Chen, Lan Nguyen, Fei Chen, Anna Greka

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The health of the kidney filtration barrier requires communication among podocytes, endothelial cells, and mesangial cells. Disruption of these cell-cell interactions is thought to contribute to disease progression in chronic kidney diseases (CKDs). Podocyte ablation via doxycycline-inducible deletion of an essential endogenous molecule, CTCF [inducible podocyte-specific CTCF deletion (iCTCFpod−/−)], is sufficient to drive progressive CKD. However, the earliest events connecting podocyte injury to disrupted intercellular communication within the kidney filter remain unclear. Single-cell RNA sequencing of kidney tissue from iCTCFpod−/− mice after 1 week of doxycycline induction was performed to generate a map of the earliest transcriptional effects of podocyte injury on cell-cell interactions at single-cell resolution. A subset of podocytes had the earliest signs of injury due to disrupted gene programs for cytoskeletal regulation and mitochondrial function. Surviving podocytes up-regulated collagen type IV ɑ5, causing reactive changes in integrin expression in endothelial populations and mesangial cells. Intercellular interaction analysis revealed several receptor-ligand-target gene programs as drivers of endothelial cell injury and abnormal matrix deposition. This analysis reveals the earliest disruptive changes within the kidney filter, pointing to new, actionable targets within a therapeutic window that may allow us to maximize the success of much needed therapeutic interventions for CKDs.

Original languageEnglish (US)
Pages (from-to)281-294
Number of pages14
JournalAmerican Journal of Pathology
Volume192
Issue number2
DOIs
StatePublished - Feb 2022
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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