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1 Pediatrics, Mount Sinai School of Medicine, New York, New York, United States
2 Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: lisa.satlin{at}mssm.edu.
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 (JNa) in CCDs by increasing channel open probability or by increasing the number of channels at the apical membrane. Both baseline and flow-stimulated JNa in CCDs were mediated by ENaC, as JNa was inhibited by benzamil. Flow-dependent increases in JNa were observed following treatment of tubules with reagents that altered membrane trafficking by disrupting microtubules (colchicine) or Golgi (brefeldin A). Furthermore, reducing luminal [Ca2+] or chelating intracellular [Ca2+] with BAPTA did not prevent the flow-dependent increase in JNa. Extracellular trypsin has been shown to activate ENaC by increasing channel open probability, and we observed that trypsin significantly enhanced JNa when tubules were perfused at a slow flow rate. However, trypsin did not further enhance JNa in CCDs perfused at fast flow rates. Similarly, the shear-induced increase in benzamil-sensitive INa in oocytes expressing protease resistance ENaC mutants was similar to that of controls. Our results suggest the rise in JNa accompanying increases in luminal flow rates reflects an increase in channel open probability.
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