Podocyte Injury in FSGS

Background: The podocyte is central to the glomerular filtration barrier and is particularly important in the disease process of focal segmental glomerulosclerosis (FSGS). The podocyte is injured in two main ways in idiopathic nephrotic syndrome. The first is by single gene disorders, such as NPHS1, NPHS2, CD2AP and TRPC6, which has led to a focus on slit-diaphragm (SD) proteins and their role in FSGS. The second type of injury is by so-called circulating factors, which target the podocyte and affect the same signalling pathways as those damaged by single gene defects, suggesting a final common damage pathway, and resulting in deranged podocyte motility. Summary: As much of our understanding on the role of the podocyte in FSGS has stemmed from the discovery of SD proteins, we will first delineate the role of SD proteins in the maintenance of the filtration barrier, how changes in SD proteins contribute to podocyte injury and their role in FSGS. We will describe our current understanding of how they communicate with intracellular signals, which is intricately linked with the maintenance of their structure, as well as podocyte dynamics and motility, which influence resistance and subsequently filtration across the glomerular filtration barrier. Key Messages: Disruptions of the SD proteins, and subsequently of the actin and microtubule cytoskeleton, are consistently seen across models of FSGS. Studies on podocytes have given us increased clarity on the pathogenesis of FSGS, where cytokine regulation, fibrogenesis, control of cell proliferation and death as well as changes in cell type appear to play key roles. (C) 2014 S. Karger AG, Basel