Podocytes in health and disease: from development to regeneration

Podocytes are highly specialized epithelial cells that are essential for maintaining the glomerular filtration barrier. They originate from the metanephric mesenchyme during kidney development, with differentiation tightly regulated by transcription factors, such as Wt1, MafB, and Lmx1b, as well as signaling pathways, including Wnt and Notch. Mature podocytes form intricate foot processes and slit diaphragms, coordinating membrane proteins, such as nephrin and podocin, with the actin cytoskeleton to ensure selective filtration. Owing to their limited regenerative capacity, podocyte injury caused by genetic mutations, mechanical stress, metabolic disorders, or inflammation leads to proteinuria, glomerulosclerosis, and the progression of chronic kidney disease. Recent studies have elucidated diverse injury mechanisms, including apoptosis, necroptosis, ferroptosis, and cytoskeletal dysregulation, highlighting aging and lipid metabolism as key modulators of podocyte vulnerability. Advances in stem cell technology and kidney organoids have enabled the modeling of podocyte development and disease, paving the way for regenerative strategies. This review provides a comprehensive overview of podocyte biology, injury mechanisms, and emerging therapeutic approaches, emphasizing translational opportunities for protecting and restoring podocyte function in kidney diseases.