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1 Department of Pediatrics, Mount Sinai School of Medicine, New York, N.Y., USA
2 Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA
3 Department of Biomedical Engineering, The City College of New York and the City University of New York Graduate School, New York, N.Y., USA
4 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: lisa.satlin{at}mssm.edu.
Autosomal recessive polycystic kidney disease (ARPKD) is characterized by the progressive dilatation of collecting ducts, the nephron segments responsible for the final renal regulation of Na, K, acid-base and water balance. Murine models of ARPKD possess mutations in genes encoding cilia-associated proteins, including Tg737 in orpk mice. New findings implicate defects in structure/function of primary cilia as central to the development of PKD. We recently reported that increases in luminal flow rate in rabbit collecting ducts increase intracellular Ca2+ concentration ([Ca2+]i) in cells therein (Liu et al., Am. J. Physiol. 285:F998, 2003). We thus hypothesized that fluid shear acting on the apical membrane or hydrodynamic bending moments acting on the cilium increase renal epithelial [Ca2+]i. To further explore this, we tested whether flow-induced [Ca2+]i transients in collecting ducts from mutant orpk mice, which possess structurally abnormal cilia, differ from those in controls. Isolated segments from 1- and 2-wk-old mice were microperfused in vitro, loaded with fura-2, and [Ca2+]i was measured by digital ratio fluorometry before and after the rate of luminal flow was increased. All collecting ducts responded to an increase in flow with an increase in [Ca2+]i , a response that appeared to be dependent on luminal Ca2+ entry. However, the magnitude of the increase in [Ca2+]i in 2- but not 1-wk-old mutant orpk animals was blunted. We speculate that this defect in mechano-induced Ca2+ signaling in orpk mice leads to aberrant structure and function of the collecting duct in ARPKD.
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