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1 Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR, USA; Portland Veterans Affairs Medical Center, Portland, OR, USA
2 Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
3 Division of Nephrology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: cohend{at}ohsu.edu.
TRPV4, a renally expressed non-selective cation channel of the transient receptor potential (TRP) family, is gated by hypotonicity. Kinases of the WNK family influence expression and function of the thiazide-sensitive Na+-Cl- chloride cotransporter, and monogenic human hypertension has been linked to mutations in the gene coding for WNK4. Along with TRPV4, WNK isoforms are highly expressed in the distal nephron. We show here that co-expression of WNK4 downregulates TRPV4 function in HEK293 cells, and this effect is mediated via decreased cell surface expression of TRPV4; total abundance of TRPV4 in whole-cell lysates is unaffected. The effect of the related kinase, WNK1, upon TRPV4 function and surface expression was similar to that of WNK4. Disease-causing point mutations in WNK4 abrogate but do not eliminate the inhibitory effect upon TRPV4 function. Unlike wild-type WNK4, a kinase-dead WNK4 point mutant failed to influence TRPV4 trafficking; however, deletion of the entire WNK4 kinase domain did not blunt the effect of WNK4 on localization TRPV4. Deletion of the extreme carboxy-terminal putative coiled coil domain of WNK4 abolished its effect. In immunoprecipitation experiments, we were unable to detect direct interaction between TRPV4 and either WNK kinase. In aggregate, these data indicate that TRPV4 is functionally regulated by WNK family kinases at the level of cell surface expression. Because TRPV4 and WNK kinases are co-expressed in the distal nephron in vivo, and because there is a tendency toward hypercalcemia in TRPV4-/- mice, we speculate that this pathway may impact systemic calcium balance. In addition, because WNK kinases and TRPV4 are activated by anisotonicity, they may comprise elements of an osmosensing or osmotically responsive signal transduction cascade in the distal nephron.
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