Mechanisms of kidney fibrosis and routes towards therapy

Single-cell genomic studies have shed light on the complex cellular and molecular mechanisms that initiate and drive kidney fibrosis, as well as on the origin of myofibroblasts, their heterogeneity, and crosstalk with other cells.Crucial fibrosis-driving cell types that have been recently identified include distinct injured/profibrotic dedifferentiated tubular epithelial cells as well as distinct macrophage subpopulations and basophils.Spatial transcriptomic technologies are rapidly being developed and add spatial information that allows the identification of the different cell types that drive disease and their crosstalk mechanisms.Integrative approaches utilizing available single-cell and spatial datasets in combination with morphology, clinical data, and novel computational approaches in large human cohorts are needed in view of considerable interindividual differences. Kidney fibrosis is the final common pathway of virtually all chronic kidney diseases (CKDs) and is therefore considered to be a promising therapeutic target for these conditions. However, despite great progress in recent years, no targeted antifibrotic therapies for the kidney have been approved, likely because the complex mechanisms that initiate and drive fibrosis are not yet completely understood. Recent single-cell genomic approaches have allowed novel insights into kidney fibrosis mechanisms in mouse and human, particularly the heterogeneity and differentiation processes of myofibroblasts, the role of injured epithelial cells and immune cells, and their crosstalk mechanisms. In this review we summarize the key mechanisms that drive kidney fibrosis, including recent advances in understanding the mechanisms, as well as potential routes for developing novel targeted antifibrotic therapeutics. Kidney fibrosis is the final common pathway of virtually all chronic kidney diseases (CKDs) and is therefore considered to be a promising therapeutic target for these conditions. However, despite great progress in recent years, no targeted antifibrotic therapies for the kidney have been approved, likely because the complex mechanisms that initiate and drive fibrosis are not yet completely understood. Recent single-cell genomic approaches have allowed novel insights into kidney fibrosis mechanisms in mouse and human, particularly the heterogeneity and differentiation processes of myofibroblasts, the role of injured epithelial cells and immune cells, and their crosstalk mechanisms. In this review we