Translational study of targeting Dynamin-1 and podocyte actin cytoskeleton to reduce proteinuria in chronic kidney disease.

Essential for podocyte function in the kidneys, Dynamin-1 (Dyn-1) is a protein composed of four domains. GTP binding and hydrolysis, necessary for membrane fission during clathrin-mediated endocytosis, are handled by its GTP hydrolase domain. Dyn-1 polymerizes into helical structures encircling vesicle necks during GTP hydrolysis, thereby facilitating membrane fission and cargo release, crucial for cell signaling and nutrient absorption. In podocytes, Dyn-1 regulates actin dynamics through interactions with actin-binding proteins, maintaining maintenance of actin cytoskeleton and cellular architecture. Dysregulation of Dyn-1 expression is implicated in foot process effacement, proteinuria, and progressive renal failure. Some of the therapeutic strategies that have been shown to enhance Dyn-1 oligomerization have been effective in the restoration of podocyte function in chronic kidney disease (CKD) models. Certain signaling pathways, including PI3K/Akt and TGF-β, are interconnected with actin dynamics, while RhoA interacts with Dyn-1 in modulating actin dynamics. Compounds such as Bis-T-23 promote Dyn-1 oligomerization and actin filament polymerization, restoring pathological podocyte structural alterations. A comprehensive understanding of Dyn-1's complex roles in podocyte structure and maintenance is needed; this is crucial for developing new strategies to protect these cells, preserve renal function, and improve the quality of life in CKD patients.