(107) CFTR loss-of-function in the kidney orchestrates tubular injury and macrophage activation, including increased TGFβ signaling

Introduction/Rationale: While cystic fibrosis (CF) affects multiple organs through dysregulated immune responses, the role of CFTR in modulating immune regulation and injury specifically within the kidney remains poorly understood. Previous work demonstrated elevated urinary markers of tubular injury in adults with CF, yet the cellular basis of this injury and its influence on the renal immune microenvironment have not been characterized.

Methods: We performed single-cell RNA sequencing (scRNA-seq) on kidneys from 2-month-old mice homozygous for the CFTR F508del mutation and wild-type controls, and validated immune-cell phenotypes by flow cytometry.

Results: ScRNA-seq revealed upregulation of wound healing and TGFβ signaling pathways (Fn1, Txnip, Jun, Itgb6) and downregulation of ion transport and metabolic pathways (Acsm2, Cyp4b1, Slc27a2) in tubular epithelial compartments, particularly the Loop of Henle, distal tubule, and collecting duct segments. CF kidneys exhibited increased total macrophage abundance with elevated Cd86 and decreased Cd163 expression, indicating a proinflammatory skew. Flow cytometry revealed decreased proliferation of MHCII+CD163hi macrophages in CF vs. WT kidneys. Finally, ligand–receptor interaction mapping identified enhanced VEGF and ANGPTL signaling between endothelial cells, fibroblasts, and tubular epithelia, and revealed upregulated TGFβ1–TGFβR1/2 signaling within macrophages, indicative of autocrine profibrotic signaling in CF kidneys.

Conclusion: Loss of CFTR function drives concurrent proinflammatory and wound-healing transcriptional programs in tubular epithelia, activating endothelium, stroma, and immune cells through paracrine mechanisms. The renal immune landscape in CF is characterized by increased macrophages with proinflammatory markers yet reduced proliferation of CD163hi M2-like macrophages, indicating dysregulated resolution that favors persistent inflammation and fibrogenesis over timely repair.