Structure of the glomerular filtration barrier

The inner surface of glomerular capillaries is decorated by a fenestrated endothelium. The glomerular basement membrane (GBM) is formed by the underlying endothelial cells and overlying visceral epithelial cells (podocytes). Podocytes cover the outer aspects of the GBM with foot processes, thin extensions with a mean width of approximately 600 nm. Podocytes are anchored in the GBM via alpha3beta1-integrins and alpha-/beta-dystroglycans. The space between neighboring foot processes is filled by the glomerular slit diaphragm, a zipper-like structure formed by a number of podocyte proteins, including nephrin, neph1–3, p-cadherin, and FAT. Other podocyte proteins are located in close vicinity of the slit diaphragm, such as the stomatin family member podocin and the ion channel TRPC6. Adapter proteins including CD2AP and Nck connect the slit diaphragm to the podocyte actin cytoskeleton. The podocyte actin-based cytoskeleton includes thick bundles of actin running inside foot processes and cortical actin decorating the inner surface of foot processes. Alpha-Actinin-4 and synaptopodin are critical cross-linkers of podocyte actin, and the large GTPase dynamin functions as a vital regulator of the podocyte actin cytoskeleton. The sialoglycoprotein podocalyxin is located at the podocyte apical surface and is thought to be the major constituent of the podocyte glycocalyx. Signaling via the urokinase receptor (uPAR) in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3-integrin.