Single Cell and Spatial Transcriptomics Define a Proinflammatory and Profibrotic Niche After Kidney Injury

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Kidney fibrosis, a common outcome of chronic kidney disease (CKD), originates from injury-induced fibrogenic niches.
• Understanding the cellular and molecular mechanisms driving kidney fibrosis is crucial for developing effective treatments.

Purpose of the Study:

• To delineate cellular heterogeneity, spatial organization, and molecular interactions within fibrotic kidney microenvironments.
• To identify key molecular players orchestrating the development of renal inflammation and fibrosis.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were employed on mouse kidneys subjected to ischemia-reperfusion injury.
• Analysis of TNC-enriched microenvironments, macrophage activation pathways (TLR4/NF-κB), and therapeutic interventions (TLR4 inhibition/knockout).

Main Results:

• A tenascin C (TNC)-enriched, proinflammatory, and profibrotic microenvironment was identified, promoting macrophage activation.
• TNC and TNC-enriched scaffolds activated bone marrow-derived macrophages via Toll-like receptor 4 (TLR4)/NF-κB signaling.
• Pharmacological inhibition or genetic knockout of TLR4 significantly alleviated renal inflammation and fibrosis by inhibiting macrophage activation.

Conclusions:

• Tenascin C (TNC) plays a critical role in establishing a proinflammatory and profibrotic niche that drives kidney fibrosis.
• Macrophage activation via the TLR4/NF-κB signaling pathway is a key mechanism in TNC-mediated renal fibrosis.
• Targeting the TNC-macrophage-TLR4 axis presents a promising therapeutic strategy for kidney fibrosis.