Actin reorganization and junctional remodeling in podocyte foot process effacement

Damage to podocytes results in kidney disease affecting millions of patients worldwide. Actin remodelling is a shared feature in podocyte FP effacement occurring after podocyte injury. However, it remains unclear which processes initiate and orchestrate cytoskeletal changes. Here, we show novel insights into actin dynamics during nephrotoxic serum nephritis and other podocyte disease models. Using Lifeact.mScarlet-I reporter expression and STED microscopy in podocytes, we could show distinct actin patterns occurring during FP effacement, independent of damage origin. Additionally, the protein composition of the slit diaphragm changed in a reversible manner. Tight junction proteins ZO-1 and Claudin-5 appeared at the plasma membrane with the onset of proteinuria. The changes in actin and junctional protein assembly during NTS nephritis were reversible as FP effacement disappeared, proteinuria declined and the podocytes recovered. For the first time, we could show with great spatial and temporal detail how the podocyte actin cytoskeleton adapts to insults and that a reversible response in slit diaphragm dynamics leads to a junctional remodelling better suited for upkeeping filtration barrier function.