TY - JOUR
T1 - Single-Cell Transcriptomics Reveal Disrupted Kidney Filter Cell-Cell Interactions after Early and Selective Podocyte Injury
AU - Clark, Abbe R.
AU - Marshall, Jamie
AU - Zhou, Yiming
AU - Montesinos, Monica S.
AU - Chen, Haiqi
AU - Nguyen, Lan
AU - Chen, Fei
AU - Greka, Anna
N1 - Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2021.11.004
DO - 10.1016/j.ajpath.2021.11.004
M3 - Article
C2 - 34861215
AN - SCOPUS:85124224102
SN - 0002-9440
VL - 192
SP - 281
EP - 294
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -