An Account of Chemical and Mechanical Regulation of TRPC6 Channels in Podocytes

Podocytes play a dynamic role in regulating glomerular filtration. The focus here is on the regulatory mechanisms of podocyte expressed transient receptor potential 6 (TRPC6) channels, an ion channel implicated in certain forms of proteinuric kidney disease. TRPC6 channels are polymodal and can be activated by either chemical or mechanical stimuli. Chemical stimulation is mediated by surface-expressed receptors, and the roles of angiotensin II type 1 receptors (AT1R), insulin receptors, and N-methyl-D-aspartate receptors (NMDAR) on TRPC6 activity are studied here. In acutely isolated rat glomeruli, angiotensin causes an upregulation of TRPC6 activity, and this is mediated by the Gαq /PLC pathway. This angiotensin-evoked upregulation is partially dependent on the formation of reactive oxygen species (ROS). In mouse podocyte cell lines, insulin causes upregulation of TRPC6 through increasing ROS formation via NADPH oxidase 4 (NOX4). Similarly, NMDAR activation upregulates TRPC6, albeit through NOX2. The previously uncharacterized podocyte NMDAR has unusual properties with strong physiological implications. Specifically, podocyte NMDA receptors are essentially unresponsive to L-glutamate and L-aspartate and do not show glycine-mediated potentiation. These receptors respond to the agonists L-homocysteate and D-aspartate with large ionic currents that are potentiated by D-serine. Given their resistance to L-glutamate-induced activation, podocyte NMDA receptors likely do not act in a localized glomerular signaling system. However, their response to ligands that circulate in both the normal and pathological state suggests a role for podocyte NMDA receptors in normal glomerular function. Receptor-driven upregulation of TRPC6 comprises a class of potential targets for prevention and treatment of multiple acquired kidney diseases. Independent of receptor-mediated response, TRPC6 channels are mechanosentive and can be activated by membrane deformation in both podocyte cell lines and isolated glomeruli. This mechanosensitivity is repressed by podocin, a cholesterol-binding, membrane-associated partner of the TRPC6 channel. In addition, podocin mediates diacylglycerol activation of TRPC6, suggesting that podocin determines the favored mode of TRPC6 activation in podocytes. It is possible that disruption of the podocin-TRPC6 complex at the slit diaphragm contributes to Ca2+ overload and eventual foot process effacement. Drugs that selectively target and suppress TRPC6 mechanosensitivity could potentially serve as treatments for glomerular diseases.