Primary cilium-dependent sensing of urinary flow and paracrine purinergic signaling

► In renal epithelium the primary cilium senses tubular flow. ► Flow triggers a cilium-dependent increase of cytosolic Ca2+. ► This increase of [Ca2+]i is greatly amplified by released ATP and autocrine P2 receptor stimulation. ► Epithelial ATP release appears physiological and is cilium-dependent. ► Released ATP inhibits tubular transport and thus acts as local diuretic. During the last 10 years or so, the renal research community has set the primary cilium into the lime light. From being viewed as a possible evolutionary rudiment, today the primary cilium has achieved the noble status of a physiologically relevant and necessary cellular structure. Its prime function in renal epithelium appears to be its ability to sense urinary flow. Much is still lacking to understand how the primary cilium senses flow. Transducer proteins, such as specific mechano-sensory ion channels, have been identified and are necessary for flow-dependent increases of epithelial [Ca2+]i. Other ciliary receptor proteins have been suggested, which may open the field of primary cilia sensing to become an even more dynamic topic of research. A flow-induced increase of [Ca2+]i has been observed in all renal and other ciliated epithelial cells. Work over the last 5 years has addressed the mechanism underlying the flow-induced increase of [Ca2+]i. It has become apparent that an initial Ca2+ influx triggers a global increase of epithelial [Ca2+]i. Eventually, it also became clear that mechanical stimulation of the epithelial cells triggers the release of ATP. Intriguingly, ATP is an auto- and paracrine signaling molecule that regulates electrolyte and water transport in the nephron by binding to apical and basolateral purinergic receptors. ATP inhibits transport at almost all sites from the proximal to the distal tubule and thus elicits a diuretic response. In the perspective of this review, the primary cilium is a sensory structure and the adequate stimulus is the mechanical deflection. The output signal is the released ATP, a paracrine factor that ultimately modulates the main function of the kidney, i.e. the enormous task of absorbing some 180L of filtrate every day.