TRPV4 channels contribute to renal myogenic autoregulation in neonatal pigs

Myogenic response, a phenomenon in which resistance size arteries and arterioles swiftly constrict or dilate in response to an acute elevation or reduction, respectively, in intravascular pressure is a key component of renal autoregulation mechanisms. Although it is well established that the renal system is functionally immature in neonates, mechanisms that regulate neonatal renal blood flow (RBF) remain poorly understood. In this study, we investigated the hypothesis that members of the transient receptor potential vanilloid (TRPV) channels are molecular components of renal myogenic constriction in newborns. We show that unlike TRPV1–3, TRPV4 channels are predominantly expressed in neonatal pig preglomerular vascular smooth muscle cells (SMCs). Intracellular Ca2+ concentration ([Ca2+]i) elevation induced by osmotic cell swelling was attenuated by TRPV4, L-type Ca2+, and stretch-activated Ca2+ channel blockers but not phospholipase A2 inhibitor. Blockade of TRPV4 channels reversed steady-state myogenic tone and inhibited pressure-induced membrane depolarization, [Ca2+]i elevation, and constriction in distal interlobular arteries. A step increase in arterial pressure induced efficient autoregulation of renal cortical perfusion and total RBF in anesthetized and mechanically ventilated neonatal pigs. Moreover, intrarenal arterial infusion of the TRPV4 channel blockers HC 067047 and RN 1734 attenuated renal autoregulation in the pigs. These data suggest that renal myogenic autoregulation is functional in neonates. Our findings also indicate that TRPV4 channels are mechanosensors in neonatal pig preglomerular vascular SMCs and contribute to renal myogenic autoregulation.

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PLA2 and TRPV4 channels regulate endothelial calcium in cerebral arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01006.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. H1390-H1397 ◽

Cited By ~ 86

Author(s):

Sean P. Marrelli ◽

Roger G. O'Neil ◽

Rachel C. Brown ◽

Robert M. Bryan

Keyword(s):

Transient Receptor Potential ◽

Cerebral Arteries ◽

Receptor Potential ◽

Ruthenium Red ◽

Transient Receptor Potential Vanilloid ◽

Middle Cerebral Arteries ◽

Trpv Channels ◽

Intracellular Ca ◽

Transient Receptor ◽

Trpv4 Channel

We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA2. In this study we examined possible mechanisms by which PLA2 regulates endothelium-dependent dilation, specifically whether PLA2 is involved in endothelial Ca2+ regulation through stimulation of TRPV4 channels. Studies were carried out with middle cerebral arteries (MCA) or freshly isolated MCA endothelial cells (EC) of male Long-Evans rats. Nitro-l-arginine methyl ester (l-NAME) and indomethacin were present throughout. In pressurized MCA, luminally delivered UTP produced increased EC intracellular Ca2+ concentration ([Ca2+]i) and MCA dilation. Incubation with PACOCF3, a PLA2 inhibitor, significantly reduced both EC [Ca2+]i and dilation responses to UTP. EC [Ca2+]i was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca2+ influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA2-sensitive Ca2+ influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA2 and a demonstrated activator of certain TRPV channels, increased both EC [Ca2+]i and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4α-phorbol 12,13-didecanoate (4αPDD), a TRPV4 channel activator, produced an increase in EC [Ca2+]i that was significantly reduced in the presence of ruthenium red. We conclude that PLA2 is involved in EC Ca2+ regulation through its regulation of TRPV4 channels. Furthermore, the PLA2-sensitive component of Ca2+ influx may be polarized to the abluminal face of the endothelium.

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TRPing on Cell Swelling - TRPV4 Senses It

Frontiers in Immunology ◽

10.3389/fimmu.2021.730982 ◽

2021 ◽

Vol 12 ◽

Author(s):

Trine L. Toft-Bertelsen ◽

Nanna MacAulay

Keyword(s):

Cell Volume ◽

Transient Receptor Potential ◽

Current Knowledge ◽

Receptor Potential ◽

Cell Swelling ◽

Transient Receptor Potential Vanilloid ◽

Volume Changes ◽

Channel Activation ◽

Volume Increase ◽

Transient Receptor

The transient receptor potential vanilloid 4 channel (TRPV4) is a non-selective cation channel that is widely expressed and activated by a range of stimuli. Amongst these stimuli, changes in cell volume feature as a prominent regulator of TRPV4 activity with cell swelling leading to channel activation. In experimental settings based on abrupt introduction of large osmotic gradients, TRPV4 activation requires co-expression of an aquaporin (AQP) to facilitate such cell swelling. However, TRPV4 readily responds to cell volume increase irrespectively of the molecular mechanism underlying the cell swelling and can, as such, be considered a sensor of increased cell volume. In this review, we will discuss the proposed events underlying the molecular coupling from cell swelling to channel activation and present the evidence of direct versus indirect swelling-activation of TRPV4. With this summary of the current knowledge of TRPV4 and its ability to sense cell volume changes, we hope to stimulate further experimental efforts in this area of research to clarify TRPV4’s role in physiology and pathophysiology.

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Dynamic coupling between TRPV4 and Ca2+-activated SK1/3 and IK1 K+ channels plays a critical role in regulating the K+-secretory BK channel in kidney collecting duct cells

AJP Renal Physiology ◽

10.1152/ajprenal.00037.2017 ◽

2017 ◽

Vol 312 (6) ◽

pp. F1081-F1089 ◽

Cited By ~ 7

Author(s):

Yue Li ◽

Hongxiang Hu ◽

Jin-Bin Tian ◽

Michael X. Zhu ◽

Roger G. O’Neil

Keyword(s):

Membrane Potential ◽

Transient Receptor Potential ◽

Collecting Duct ◽

Critical Role ◽

Receptor Potential ◽

Bk Channel ◽

Transient Receptor Potential Vanilloid ◽

Cortical Collecting Duct ◽

Intracellular Ca ◽

Transient Receptor

The large-conductance Ca2+-activated K+ channel, BK (KCNMA1), is expressed along the connecting tubule (CNT) and cortical collecting duct (CCD) where it underlies flow- and Ca2+-dependent K+ secretion. Its activity is partially under the control of the mechanosensitive transient receptor potential vanilloid type 4 (TRPV4) Ca2+-permeable channel. Recently, we identified three small-/intermediate-conductance Ca2+-activated K+ channels, SK1 (KCNN1), SK3 (KCNN3), and IK1 (KCNN4), with notably high Ca2+-binding affinities, that are expressed in CNT/CCD and may be regulated by TRPV4-mediated Ca2+ influx. The K+-secreting CCD mCCDcl1 cells, which express these channels, were used to determine whether SK1/3 and IK1 are activated on TRPV4 stimulation and whether they contribute to Ca2+ influx and activation of BK. Activation of TRPV4 (GSK1016790A) modestly depolarized the membrane potential and robustly increased intracellular Ca2+, [Ca2+]i. Inhibition of both SK1/3 and IK1 by application of apamin and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), respectively, further depolarized the membrane potential and markedly suppressed the TRPV4-mediated rise in [Ca2+]i. Application of BK inhibitor iberiotoxin after activation of TRPV4 without apamin/TRAM-34 also reduced [Ca2+]i and further intensified membrane depolarization, demonstrating BK involvement. However, the BK-dependent effects on [Ca2+]i and membrane potential were largely abolished by pretreatment with apamin and TRAM-34, identical to that observed by separately suppressing TRPV4-mediated Ca2+ influx, demonstrating that SK1/3-IK1 channels potently contribute to TRPV4-mediated BK activation. Our data indicate a direct correlation between TRPV4-mediated Ca2+ signal and BK activation but where early activation of SK1/3 and IK1 channels are critical to sufficiently enhanced Ca2+ entry and [Ca2+]i levels required for activation of BK.

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