The role of podocyte cGMP signalling in glomerular crosstalk and states of volume overload

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Podocytes are specialized cells of the kidney filter and possess a complex cytoskeletal architecture with delicate secondary foot processes. So far, our knowledge about cGMP signaling in podocytes is quite limited. The cGMP signaling cascades are mediated by two main pathways. Volume overload triggers the production of natriuretic peptides in the heart and leads to increased fluid excretion in the kidney, while endothelial shear stress triggers NO production and relaxation of vascular smooth muscle cells. Our preliminary data demonstrates that both pathways increase podocyte cGMP concentration and suggests that podocytes respond to NO produced in endothelial cells. We will utilize acute kidney slices, intravital multiphoton imaging and a genetically encoded cGMP sensor to visualize cGMP levels in podocytes and to characterize triggers of cGMP signaling in podocytes in vivo. Furthermore, we will study alterations of cGMP signaling in disease states and investigate the impact of pharmacological interventions on the cGMP signaling pathways. We will put a special emphasis on investigating the newly discovered NO mediated endothelial-to-podocyte crosstalk in health and disease conditions, including an eNOS knock-out mouse line, and use a model of volume overload, a strong stimulus of natriuretic peptide signaling, to elucidate the role of the two main cGMP generating signaling pathways.