The concept of fluid flow-induced nucleotide release was first suggested from research in vascular biology. Fluid flow elicits regulatory input signals in vascular endothelial cells. In response to shear stress, these cells release vasoactive autacoids (e.g. nitric oxide) (Moncada and Higgs, 2006). Mechanical perturbations are known to release nucleotides such as ATP and UTP from most cells, including endothelial and epithelial cells (Bodin et al. 1991; Lazarowski et al. 2003). In endothelia, extracellular ATP triggers nitric oxide release. More recently, the concept of endothelial shear stress-induced vasodilatation has been suggested to involve ATP release and endothelial purinergic receptors (P2X4 isoform) (Yamamoto et al. 2006). Endothelial and epithelial cells abundantly express purinergic receptors (P2). These receptors are localized to both the apical (lumen-facing) and basolateral sides of the epithelial barrier where they modulate transepithelial salt and water transport (Leipziger, 2003). The rate of fluid flow over the apical surface of epithelia varies widely under different physiological conditions (e.g. diuresis and antidiuresis in the renal tubule). The question is how epithelial cells coordinate ion transport and fluid flow. Many researchers have become fascinated by the possible role of the primary cilium as a cellular sensing organelle in epithelia (Praetorius & Spring, 2005). In the absence of fluid flow, the primary cilium protrudes into the epithelial lumen perpendicular to the cell membrane. Fluid flow triggers cilium bending, eliciting an increase of cytosolic Ca2+ ([Ca2+]i) (Praetorius & Spring, 2001, 2003). Thus, this organelle appears to have the capacity to be a sensory antenna to detect flow changes. The flow-induced [Ca2+]i increase, a hallmark of this novel epithelial function, is found in many epithelial tissues. The nature of this flow-stimulated [Ca2+]i increase is not currently fully understood. It was hypothesized to relate to influx of Ca2+ via the polycystin1/2 complex localized on the primary cilium (Nauli et al. 2003; Xu et al. 2007). Recently it was found that the flow-induced increase of [Ca2+]i in isolated perfused renal tubules is caused or augmented by a flow or stretch-induced release of nucleotides from the epithelial cells and paracrine activation of epithelial P2 receptors (Jensen et al. 2007). It is very likely that this process requires mechano-sensing via the primary cilium, but this remains to be proven. In bile duct epithelia, extracellular nucleotides provide autocrine/paracrine stimuli for anion secretion (Feranchak & Fitz, 2002). Like in renal epithelia, native perfused bile ducts were recently shown to respond with an increase of [Ca2+]i after increasing ductal flow in a cilium-dependent manner (Masyuk et al. 2006). In this issue of The Journal of Physiology, Woo et al. (2008) present direct evidence that fluid flow over the apical surface of cultured rat and human bile duct epithelial cells triggers shear-stress-dependent ATP release to the apical side of the tissue. At the same time, fluid flow also triggers an increase of [Ca2+]i and hence, the activation of Cl− secretion. These data highlight that ATP is released from the epithelial cells, themselves, and that fluid flow, itself, stimulates epithelial ATP secretion. Based on these data, Woo et al. (2008) propose an integrative cellular model of bile secretion (see Fig. 10 of their paper). In this model, augmented hepatic bile secretion carries a signal via luminal bile flow to the target site of the bile duct cell. This cell uses its property to sense flow and triggers the release of nucleotides, which activate luminal (and probably also basolateral) P2 receptors in the duct cell leading to an increase of [Ca2+]i. Elevated [Ca2+]i in turn activates ductal anion secretion, which is a major component of bile formation. As Woo et al. (2008) mostly use non-ciliated human bile duct cells their results argue that this mechanism does not require the primary cilium. Interestingly, in ciliated rat bile duct cells the flow-induced ATP secretion response curve is shifted to the left (Woo et al. 2008), suggesting that primary cilia accentuate the detection of flow changes by epithelia. Finally, the data of Woo et al. (2008) suggest that the activation of the atypical PKCζ is involved in flow-stimulated epithelial ATP secretion. Epithelial P2 receptors modulate ion transport in a dual fashion. In secretory epithelia (e.g. the bile duct), P2 receptors activate ion secretion, whereas in absorptive epithelia (e.g. the renal tubule), they inhibit absorption. Thus, the overall functional consequence of epithelial P2 receptor stimulation is to promote an increased amount of fluid in the tubular compartment. The flow-induced secretion of ATP now found in renal and bile duct epithelia has a fascinating general perspective: flow changes per se, via local puringeric signalling, regulate the amount of ion and water transport in many epithelia. This novel concept of flow-sensing and ion transport regulation implies that local physical conditions define the final quantity and composition of the transported fluids.
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Jul 5, 2021
Wuttipong Phumrattanaprapin + 8
Open Access
