Mechanoregulation of intracellular Ca2+ concentration is attenuated in collecting duct of monocilium-impaired orpk mice.

Abstract

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 Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](i). To further explore this, we tested whether flow-induced [Ca(2+)](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; [Ca(2+)](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 [Ca(2+)](i), a response that appeared to be dependent on luminal Ca(2+) entry. However, the magnitude of the increase in [Ca(2+)](i) in 2- but not 1-wk-old mutant orpk animals was blunted. We speculate that this defect in mechano-induced Ca(2+) signaling in orpk mice leads to aberrant structure and function of the collecting duct in ARPKD.

• Authors: Wen Liu, Noel S Murcia, Yi Duan, Sheldon Weinbaum, Bradley K Yoder, Erik Schwiebert, Lisa M Satlin
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 289 Issue 5 Pg. F978-88 (Nov 2005) ISSN: 1931-857X [Print] United States
• PMID: 15972389 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fluorescent Dyes
• Tg737Rpw protein, mouse
• Tumor Suppressor Proteins
• Calcium
• Fura-2

Topics

• Animals
• Calcium (pharmacokinetics)
• Cilia (pathology)
• Dilatation, Pathologic
• Fluorescent Dyes
• Fluorometry
• Fura-2
• Kidney Tubules, Collecting (physiology)
• Mice
• Mutation
• Polycystic Kidney, Autosomal Recessive (physiopathology)
• Tumor Suppressor Proteins (genetics, physiology)
• Urodynamics