Critical Role of Dysregulated Autophagy in Pathophysiology of Podocytopathy

Podocytopathies are glomerular disorders characterized by podocyte injury, typically resulting in marked proteinuria. Podocytes are highly specialized, terminally differentiated epithelial cells essential for maintaining the structural and functional integrity of the glomerular filtration barrier. Owing to constant exposure to injurious stimuli, podocytes may undergo dedifferentiation, hypertrophy, apoptosis, or necrosis. Autophagy is a key cytoprotective mechanism that enables cells to degrade and recycle damaged or unnecessary components through a multistep process involving induction, autophagosome formation, fusion with lysosomes, and degradation. Under physiologic conditions, podocytes exhibit high basal levels of autophagy, which are essential for clearing aberrant cytoplasmic elements, including inflammasomes. Both experimental and clinical studies have demonstrated that dysregulated autophagy is a common feature in various podocytopathies, including minimal change disease, FSGS, membranous nephropathy, diabetic nephropathy, and lupus nephritis. Restoration of autophagic activity through natural or pharmacologic inducers-such as mechanistic target of rapamycin inhibitors, metformin, or mineralocorticoid receptor antagonists-has been associated with reduced proteinuria and improved podocyte function. Despite strong preclinical evidence, clinical trials investigating autophagy-targeting therapies in podocytopathies remain limited and often lack long-term follow-up. Moreover, the clinical use of some promising agents is constrained by significant adverse effects, underscoring the need for safer, more targeted therapeutic strategies.