TRPV4 as a flow sensor in flow-dependent K⁺ secretion from the cortical collecting duct

Abstract

The transient receptor vanilloid-4 (TRPV4) is a mechanosensitive, swell-activated cation channel that is abundant in the renal distal tubules. Immunolocalization studies, however, present conflicting data as to whether TRPV4 is expressed along the apical and/or basolateral membranes. To disclose the role of TRPV4 in flow-dependent K(+) secretion in distal tubules in vivo, urinary K(+) excretion and net transports of K(+) and Na(+) in the cortical collecting duct (CCD) were measured with an in vitro microperfusion technique in TRPV4(+/+) and TRPV4(-/-) mice. Both net K(+) secretion and Na(+) reabsorption were flow dependently increased in the CCDs isolated from TRPV4(+/+)mice, which were significantly enhanced by a luminal application of 50 microM 4alpha-phorbol-12,13-didecanoate (4alphaPDD), an agonist of TRPV4. No flow dependence of net K(+) and Na(+) transports or effects of 4alphaPDD on CCDs were observed in TRPV4(-/-) mice. A basolateral application of 4alphaPDD had little effect on these ion transports in the TRPV4(+/+) CCDs, while the luminal application did. Urinary K(+) excretion was significantly smaller in TRPV4(-/-) than in TRPV4(+/+) mice when urine production was stimulated by a venous application of furosemide. These observations suggested an essential role of the TRPV4 channels in the luminal or basolateral membrane as flow sensors in the mechanism underlying the flow-dependent K(+) secretion in mouse CCDs.

Discrete Control of TRPV4 Channel Function in the Distal Nephron by Protein Kinases A and C

“…Indeed, our group recently demonstrated that genetic ablation of TRPV4 abolishes flow-dependent [Ca 2ϩ ] i responses in microdissected distal nephron preparations (12). Consistently, flow-dependent K ϩ secretion in the distal nephron, a Ca 2ϩ -dependent process utilizing the maxi-K channel (13,14), is absent in TRPV4 knock-out animals (15).…”

“…Adequate mechanosensitive [Ca 2ϩ ] i responses are important determinants of many physiological processes in late nephron segments, including flow-dependent K ϩ secretion (15,25), regulatory volume decreases (26), etc. Furthermore, we and others have recently demonstrated that pharmacological stimulation of TRPV4 activity is instrumental for blunting renal cystogenesis in ARPKD models (18,27).…”

Protein Kinase G Inhibits Flow-Induced Ca2+ Entry into Collecting Duct Cells

“…These candidate channels include TRPV4, 7,8 TRPP1-P2 complex, 9 heteromeric TRPV4-P2, 10 and heteromeric TRPV4-C1. 11 Our coimmunoprecipitation and double immunostaining experiments showed the physical association of TRPV4 and TRPP2.…”

“…2,6 There is intense interest in searching for the plasma membrane channels that mediate flow-induced Ca 2+ entry in renal epithelial cells. Several candidate channels have been proposed, including transient receptor potential vanilloid 4 (TRPV4), 7,8 transient receptor potential polycystin 1 (TRPP1)-TRPP2 complex, 9 and heteromeric TRPV4-P2 channels. 10 It is suggested that TRPP1 and TRPP2 may form a physical complex in which TRPP1 serves as a sensor to transduce the flow stimuli to TRPP2, which is a Ca 2+ entry channel.…”

IP3 Receptor Binds to and Sensitizes TRPV4 Channel to Osmotic Stimuli via a Calmodulin-binding Site

“…TRPV4 participation in osmo-and mechanotransduction (1,2) contributes to important functions including cellular (3,4) and systemic volume homeostasis (5,6), arterial dilation (7,8), nociception (9), epithelial hydroelectrolyte transport (10,11), bladder voiding (12), and ciliary beat frequency regulation (13)(14)(15). TRPV4 also responds to temperature (16,17), endogenous arachidonic acid (AA) metabolites (18), and phorbol esters including the inactive 4␣-phorbol 12,13-didecanoate (4␣PDD) (19,20) and participates in receptor-operated Ca 2ϩ entry (15), thus showing multiple modes of activation.…”