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Mechanism underlying flow stimulation of sodium absorption in the mammalian collecting duct

¹Division of Pediatric Nephrology, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York; and ²Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 21 December 2005 ; accepted in final form 22 March 2006

Vectorial Na⁺ absorption across the aldosterone-sensitive distal nephron plays a key role in the regulation of extracellular fluid volume and blood pressure. Within this nephron segment, Na⁺ diffuses from the urinary fluid into principal cells through an apical, amiloride-sensitive, epithelial Na⁺ channel (ENaC), which is considered to be the rate-limiting step for Na⁺ absorption. We have reported that increases in tubular flow rate in microperfused rabbit cortical collecting ducts (CCDs) lead to increases in net Na⁺ absorption and that increases in laminar shear stress activate ENaC expressed in oocytes by increasing channel open probability. We therefore examined whether flow stimulates net Na⁺ absorption (J_Na) in CCDs by increasing channel open probability or by increasing the number of channels at the apical membrane. Both baseline and flow-stimulated J_Na in CCDs were mediated by ENaC, as J_Na was inhibited by benzamil. Flow-dependent increases in J_Na were observed following treatment of tubules with reagents that altered membrane trafficking by disrupting microtubules (colchicine) or Golgi (brefeldin A). Furthermore, reducing luminal Ca²⁺ concentration ([Ca²⁺]) or chelating intracellular [Ca²⁺] with BAPTA did not prevent the flow-dependent increase in J_Na. Extracellular trypsin has been shown to activate ENaC by increasing channel open probability, and we observed that trypsin significantly enhanced J_Na when tubules were perfused at a slow flow rate. However, trypsin did not further enhance J_Na in CCDs perfused at fast flow rates. Similarly, the shear-induced increase in benzamil-sensitive J_Na in oocytes expressing protease resistance ENaC mutants was similar to that of controls. Our results suggest the rise in J_Na accompanying increases in luminal flow rates reflects an increase in channel open probability.

epithelial sodium channel; in vitro microperfusion; protein trafficking; mechanoregulation; laminar shear; principal cell

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