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1 Department of Pediatrics, Mount Sinai School of Medicine, New York, N.Y., USA
2 Department of Mechanical Engineering and Center for Biomedical Engineering, City College of New York, New York, N.Y., USA
* To whom correspondence should be addressed. E-mail: lisa.satlin{at}mssm.edu.
An acute increase in tubular fluid flow rate in the microperfused CCD, associated with a ~20% increase in tubular diameter, leads to an increase in intracellular Ca2+ concentration ([Ca2+]i) in both principal and intercalated cells comprising this segment (Am. J. Physiol. 283:F437, 2002). The apical cilium present in principal but not intercalated cells has been proposed to be a flow sensor. We sought to determine whether flow across the cilium and/or epithelial stretch mediates the flow-induced [Ca2+]i transient in CCD cells. To examine this, CCDs from NZW rabbits were microperfused in vitro, split-open (to isolate the effect of flow across the cilium), or occluded (to examine the effect of circumferential stretch and the duration/magnitude of the flow impulse) and loaded with fura-2 for measurement of [Ca2+]i. In perfused and occluded CCDs, a rapid (<1 sec) but not slow (>3 min) increase in luminal flow rate and/or circumferential stretch led to a ~3-fold increase in [Ca2+]i in both principal and intercalated cells, with peak [Ca2+]i reached within 10 sec. This response was mediated by external Ca2+ entry and IP3-mediated release of cellular Ca2+ stores. In split-open CCDs, an increase in superfusate flow rate led to a ~2-fold increase in [Ca2+]i in both cell populations, with a time delay to peak [Ca2+]i of ~30 sec. These experimental findings are interpreted with the aid of mathematical models, used to predict the fluid stress on the apical membranes of the CCD cells and the forces and torques on and deformation of the primary cilia. We conclude that rapid increases in luminal flow rate and circumferential stretch of the CCD, leading to shear or hydrodynamic impulses at the cilium or apical membrane, lead to increases in [Ca2+]i in both principal and intercalated cells.
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