期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 289, 期 5, 页码 F978-F988出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00260.2004
关键词
autosomal recessive polycystic kidney disease; calcium signaling; principal cell; intercalated cell; differentiation
资金
- NIDDK NIH HHS [DK-38470, DK-51391, P30 DK074038, DK-065655, DK-57306] Funding Source: Medline
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 sodium, potassium, 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 polycystic kidney disease. Our group (Liu W, Xu S, Woda C, Kim P, Weinbaum S, and Satlin LM, Am J Physiol Renal Physiol 285: F998-F1012, 2003) recently reported that increases in luminal flow rate in rabbit collecting ducts increase intracellular Ca2+ concentration ([Ca2+](i)) in cells therein. 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 and loaded with fura 2; [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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