Endothelial-to-Mesenchymal Transition in Chronic Kidney Disease: Mechanisms and Therapeutic Targets

Renal fibrosis is the final common pathological outcome of chronic kidney disease (CKD) and a major driver of progression to end-stage kidney disease. Endothelial-to-mesenchymal transition (EndMT) is a phenotypic process in which endothelial cells lose their endothelial identity and acquire mesenchymal or myofibroblast-like characteristics, thereby contributing to extracellular matrix accumulation, capillary rarefaction, microvascular dysfunction, and fibrotic remodeling.

Transforming growth factor-β (TGF-β) is a central inducer of EndMT through canonical Smad-dependent and noncanonical Smad-independent signaling pathways. Additional pathways, including Wnt/β-catenin, Notch, Hedgehog, inflammatory cytokine signaling, autophagy dysregulation, oxidative stress, and metabolic reprogramming, further regulate EndMT in the diseased kidney. This review summarizes the cellular and molecular mechanisms underlying EndMT in CKD, highlights interactions among major regulatory pathways, and discusses emerging pharmacological strategies to inhibit EndMT, preserve renal microvascular integrity, and attenuate fibrogenesis.

Growing evidence supports an important role for EndMT in renal fibrosis and CKD progression. However, the quantitative contribution of EndMT to human kidney fibrosis, the biological significance of partial or hybrid EndMT states, and the most effective approaches for therapeutically targeting this process remain incompletely defined. Advances in lineage-tracing, single-cell and spatial transcriptomics, biomarker development, and pathway-selective therapies will be essential for translating EndMT-directed interventions into clinical practice.