Renal tubular flow rates vary over time. Consequently, tubular epithelial cells are subjected to changes in hydrostatic pressure, membrane stretch and shear stress that ultimately affect cellular functions. Similarly, inflation of the urinary bladder subjects bladder epithelial cells to changes in hydrostatic pressure and membrane stretch. Epithelial Na channels (ENaC) and K secretory channels are present in the apical membrane of cortical collecting ducts (CCDs) and have key roles in transepithelial Na absorption and K secretion, respectively. CCDs respond to increases in flow with increases in both Na absorption as a result of activation of ENaCs, as well as increases in K secretion via TEA- and charybdotoxin-sensitive maxi K channels, suggesting that biomechanical forces activate both ENaC and maxi K channels. Urinary bladder inflation is also associated with activation of both ENaCs as well as charybdotoxin-sensitive K channels. This application will address the mechanism underlying the flow/stretch-dependence of ENaC and maxi K activation. Proposed studies will utilize CCDs, urinary bladders, and cultured epithelial cells to determine whether flow/stretch-mediated increases in Na absorption and K secretion result from increases in numbers (N) of Na and maxi K channels residing at the apical membrane, or from increases in channel open probability. The role of extracellular signaling molecules released in response to mechanical stimuli in modulating ENaC and maxi K activity will be defined, as will the role of intracellular Ca in modulating the response of maxi K channels to flow/stretch. These proposed studies should provide new information regarding the regulation of solute transport in the CCD and urinary bladder, and provide a framework for understanding the mechanisms of altered solute transport associated with disorders of the extracellular fluid volume.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK051391-07
Application #
6544213
Study Section
Special Emphasis Panel (ZRG1-SMB (03))
Program Officer
Ketchum, Christian J
Project Start
1996-05-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
7
Fiscal Year
2002
Total Cost
$370,529
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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