The challenge and response of podocytes to glomerular hypertension

Glomerular hypertension (ie, increased glomerular capillary pressure), has been shown to cause podocyte damage progressing to glomerulosclerosis in animal models. Increased glomerular capillary pressure results in an increase in wall tension that acts primarily as circumferential tensile stress on the capillary wall. The elastic properties of the glomerular basement membrane (GBM) and the elastic as well as contractile properties of the cytoskeleton of the endothelium and of podocyte foot processes resist circumferential tensile stress. Whether the contractile forces generated by podocytes are able to equal circumferential tensile stress to effectively counteract wall tension is an open question. Mechanical stress is transmitted from the GBM to the actin cytoskeleton of podocyte foot processes via cell-matrix contacts that contain mainly integrin α3β1 and a variety of linker, scaffolding, and signaling proteins, which are not well characterized in podocytes. We know from in vitro studies that podocytes are sensitive to stretch, however, the crucial mechanosensor in podocytes remains unclear. On the other hand, in vitro studies have shown that in stretched podocytes specific signaling cascades are activated, the synthesis and secretion of various hormones and their receptors are increased, cell-cycle arrest is reinforced, cell adhesion is altered through secretion of matricellular proteins and changes in integrin expression, and the actin cytoskeleton is reorganized in a way that stress fibers are lost. In summary, current evidence suggests that in glomerular hypertension podocytes primarily aim to maintain the delicate architecture of interdigitating foot processes in the face of an expanding GBM area.