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1 Integrative Biology & Pharmacology, The University of Texas Health Science Center, Houston, Texas, United States
2 Otolaryngology-HNS, Stanford University School of Medicine, Stanford, California, United States
* To whom correspondence should be addressed. E-mail: roger.g.oneil{at}uth.tmc.edu.
Gain/loss of function studies were utilized to assess the potential role of the endogenous TRPV4 as a sensor of flow and osmolality in M-1 collecting duct cells (CCD). TRPV4 mRNA and protein were detectable in M-1 cells and stably transfected HEK 293 cells where the protein occurred as a glycosylated doublet on Western blots. Immunofluorescence imaging demonstrated expression of TRPV4 at the cell membranes of TRPV4-HEK and M-1 cells, and at the luminal membrane of mouse kidney CCD. Using intracellular calcium imaging techniques, calcium influx was monitored in cells grown on coverslips. Application of known activators of TRPV4, including 4
-PDD and hypotonic media, induced strong calcium influx in M-1 cells and TRPV4-transfected HEK 293 cells, but not in non-transfected cells. Applying increased flow/shear stress in a parallel plate chamber induced calcium influx in both M-1 and TRPV4-transfected HEK cells, but not in non-transfected HEK cells. Further, in loss of function studies employing siRNA knockdown techniques, transfection of both M-1 and TRPV4 transfected HEK cells with siRNA specific for TRPV4, but not to an inappropriate siRNA, led to a time-dependent decrease in TRPV4 expression which was accompanied by a loss of stimuli-induced calcium influx to flow and hypotonicity. It is concluded that TRPV4 displays a mechanosensitive nature with activation properties consistent with a molecular sensor of both fluid flow (or shear stress) and osmolality, or a component of a sensor complex, in flow-sensitive renal collecting duct cells.
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