Membrane Tension Modulates the Effects of Apical Cholesterol on the Renal Epithelial Sodium Channel

Wei, Shipeng; Li, Xueqi; Chou, Chu-Fang; Liang, You‐You; Peng, Ji‐Bin; Warnock, David G.; Ma, Heping

doi:10.1007/s00232-007-9071-7

Cited by 20 publications

(21 citation statements)

References 42 publications

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“…In four similar recordings the single channel conductance calculated for the reduced and the full channel openings averaged 3.04 ± 0.11 pS and 5.71 ± 0.04 pS (n=4, N=2), respectively. Our observation that MβCD pretreatment may cause the appearance of ENaC conductance sublevels in at least some of the patches is in good agreement with a recent report that ENaC subconductance events were observed in A6 cells after treatment with 50 mM MβCD [49]. Collectively, our findings indicate that cholesterol removal has significant effects on the single channel properties of ENaC.…”

Section: Effect Of Cholesterol Removal On Single Channel Properties Osupporting

confidence: 82%

“…This is in good agreement with recent findings [7] that membrane cholesterol extraction did not significantly affect the electrophysiological parameters of A6 renal epithelial cells under steady-state conditions. Some studies suggested that a high cholesterol content of the plasma membrane tends to stabilize ENaC function [49]. In contrast, reducing plasma membrane cholesterol was reported to impair ENaC function but with rather variable effects [7,8,49,52].…”

Section: Discussionmentioning

confidence: 99%

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Cholesterol Depletion of the Plasma Membrane Prevents Activation of the Epithelial Sodium Channel (ENaC) by SGK1

Krueger¹,

Haerteis²,

Yang³

et al. 2009

Cell Physiol Biochem

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The lipid environment of the epithelial sodium channel (ENaC) and its possible association with so-called lipid rafts may be relevant to its function. The aim of our study was to confirm the association of ENaC with lipid rafts and to analyze the effect of cholesterol depletion of the plasma membrane by methyl-β-cyclodextrin (MβCD) on channel function and regulation. Using sucrose density gradient centrifugation we demonstrated that a significant portion of ENaC protein distributes to low density fractions thought to be typical lipid raft fractions. Importantly, cholesterol depletion of cell lysate by MβCD shifted ENaC to non-raft fractions of higher density. Live cell imaging demonstrated that treatment with MβCD largely reduced filipin staining over time, confirming cholesterol depletion of the plasma membrane. For electrophysiological studies intact oocytes were exposed to 20 mM MβCD for three hours. MβCD treatment had no consistent effect on baseline whole-cell ENaC currents. In addition to the typical single channel conductance of about 5 pS, subconductance states of ENaC were occasionally observed in patches from MβCD treated but not from control oocytes. Importantly, in outside-out patch clamp recordings the stimulatory effect of recombinant SGK1 in the pipette solution was essentially abolished in oocytes pretreated with MβCD. These results indicate that ENaC activation by cytosolic SGK1 is compromised by removing cholesterol from the plasma membrane. Thus, ENaC activation by SGK1 may require the presence of an intact lipid environment and/or of lipid rafts as signalling platform.

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Section: Effect Of Cholesterol Removal On Single Channel Properties Osupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Cholesterol Depletion of the Plasma Membrane Prevents Activation of the Epithelial Sodium Channel (ENaC) by SGK1

Krueger¹,

Haerteis²,

Yang³

et al. 2009

Cell Physiol Biochem

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“…In addition to ROMK1, ENaC is also regulated by cholesterol 34,35 and PI(4,5)P 2 . [36][37][38] However, unlike ROMK1 channels, ENaC appears to be localized in microvilli.…”

Section: Discussionmentioning

confidence: 99%

Lovastatin-Induced Phosphatidylinositol-4-Phosphate 5-Kinase Diffusion from Microvilli Stimulates ROMK Channels

Liu

Yang

et al. 2015

Journal of the American Society of Nephrology

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We recently showed that lovastatin attenuates cyclosporin A (CsA)-induced damage of cortical collecting duct (CCD) principal cells by reducing intracellular cholesterol. Previous studies showed that, in cell expression models or artificial membranes, exogenous cholesterol directly inhibits inward rectifier potassium channels, including Kir1.1 (Kcnj1; the gene locus for renal outer medullary K + [ROMK1] channels). Therefore, we hypothesized that lovastatin might stimulate ROMK1 by reducing cholesterol in CCD cells. Western blots showed that mpkCCD c14 cells express ROMK1 channels with molecular masses that approximate the molecular masses of ROMK1 in renal tubules detected before and after treatment with DTT. Confocal microscopy showed that ROMK1 channels were not in the microvilli, where cholesterolrich lipid rafts are located, but rather, the planar regions of the apical membrane of mpkCCD c14 cells. Furthermore, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ], an activator of ROMK channels, was detected mainly in the microvilli under resting conditions along with the kinase responsible for PI(4,5) P 2 synthesis, phosphatidylinositol-4-phosphate 5-kinase, type I g [PI(4)P5K I g], which may explain the low basal open probability and increased sensitivity to tetraethylammonium observed here for this channel. Notably, lovastatin induced PI(4)P5K I g diffusion into planar regions and elevated PI(4,5)P 2 and ROMK1 open probability in these regions through a cholesterol-associated mechanism. However, exogenous cholesterol alone did not induce these effects. These results suggest that lovastatin stimulates ROMK1 channels, at least in part, by inducing PI(4,5)P 2 synthesis in planar regions of the renal CCD cell apical membrane, suggesting that lovastatin could reduce cyclosporin-induced nephropathy and associated hyperkalemia.

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“…Therefore, ENaC is proposed as the key mediator of aldosterone-dependent BP control in the endothelium [80] . Several studies, in different cell types including CCD and endothelial cells, have suggested that ENaC may function as a mechanosensor and that mechanical stimuli may activate ENaC [22,81,82] . Because endothelial ENaC inhibition may activate nitric oxide (NO) synthase [83] , it is completely possible that altered blood flow (shear stress), which is caused by over reabsorption of Na + via ENaC located at distal nephron, may affect the NO production in endothelia.…”

Section: The Molecular Variations In Enac and The Risk For Developingmentioning

confidence: 99%

Role of the epithelial sodium channel in salt-sensitive hypertension

et al. 2011

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The epithelial sodium channel (ENaC) is a heteromeric channel composed of three similar but distinct subunits, α, β and γ. This channel is an end-effector in the rennin-angiotensin-aldosterone system and resides in the apical plasma membrane of the renal cortical collecting ducts, where reabsorption of Na + through ENaC is the final renal adjustment step for Na + balance. Because of its regulation and function, the ENaC plays a critical role in modulating the homeostasis of Na + and thus chronic blood pressure. The development of most forms of hypertension requires an increase in Na + and water retention. The role of ENaC in developing high blood pressure is exemplified in the gain-of-function mutations in ENaC that cause Liddle's syndrome, a severe but rare form of inheritable hypertension. The evidence obtained from studies using animal models and in human patients indicates that improper Na + retention by the kidney elevates blood pressure and induces salt-sensitive hypertension.

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Membrane Tension Modulates the Effects of Apical Cholesterol on the Renal Epithelial Sodium Channel

Cited by 20 publications

References 42 publications

Cholesterol Depletion of the Plasma Membrane Prevents Activation of the Epithelial Sodium Channel (ENaC) by SGK1

Cholesterol Depletion of the Plasma Membrane Prevents Activation of the Epithelial Sodium Channel (ENaC) by SGK1

Lovastatin-Induced Phosphatidylinositol-4-Phosphate 5-Kinase Diffusion from Microvilli Stimulates ROMK Channels

Role of the epithelial sodium channel in salt-sensitive hypertension

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