醛固酮快速调控肾上皮细胞钠通道作用的研究
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摘要
研究目的：醛固酮在调节细胞外液，维持电解质平衡以及控制血压稳定的过程中发挥着重要的作用，醛固酮重要的生理功能有赖于通过调控肾上皮钠通道（ENaC）对钠的重吸收，目前已知相关的作用机制分为基因组作用和非基因组作用。其中，研究较清楚的是醛固酮的基因组作用方式：醛固酮进入集合管主细胞后，与胞浆内的盐皮质激素受体(mineralocorticoid receptor，MR)结合，形成激素-受体复合体，后者进入细胞核与核中DNA特异性结合位点相互作用，调节特异性mRNA转录，最终合成多种醛固酮诱导蛋白(aldosterone-induced protein, AIP)，使管腔膜(apicalside)ENaC活性增强，基侧膜(basolateral side)钠钾泵的活性增加，从而促进跨上皮细胞的Na＋重吸收。醛固酮基因组作用的特点是作用起效较慢，作用时间长，对MR阻断剂敏感。此外,醛固酮还可发挥快速的非基因组作用来调控Na+的重吸收，此作用的特点为起效迅速,对MR阻断剂不敏感,但其内在机制还知之甚少。因此研究醛固酮非依赖MR快速调控ENaC的作用及其相关的作用机制，有助于进一步全面了解醛固酮调节ENaC作用的生理、病理意义，同时也可促进新型醛固酮拮抗药物的研发，为醛固酮快速作用提供可能的应对措施。
主要内容：
1建立具有ENaC活性的哺乳动物肾上皮细胞模型并进行评价。
2研究醛固酮快速调控ENaC的作用。
3探讨醛固酮快速调控ENaC的可能机制。
研究方法：
1．实验细胞模型的建立
建立具有ENaC活性的哺乳动物肾上皮细胞模型-选择MDCK（Madin-Darbycanine kidney）、mpkCCD（mouse principle cell of kidney in cortical collecting duct）两种细胞株，培养成具有完整膜，有极性，高阻抗，阿米洛利敏感的细胞模型,最后通过观察细胞形态结构、测量跨膜电阻值、测量细胞单通道记录三个方面来评估，择优选出适合进一步实验的理想细胞模型。
2．醛固酮对ENaC的快速调控作用
给予醛固酮(10-6M/L)作用于mpkCCD细胞模型，观察醛固酮对细胞形态结构、阿米洛利敏感的跨膜电阻、胞内钙离子浓度、单通道离子电流的影响。使用MR阻断剂螺内酯以及醛固酮转录、蛋白合成抑制剂，验证醛固酮对ENaC快速（＜3小时）调节作用主要是非依赖MR的非基因组作用。
3．醛固酮对ENaC作用机制的研究
（1）通过使用PI3-K通路特异性的阻断剂LY294002(50um/L)验证PI3-K通路在醛固酮快速调控ENaC过程中的作用。
（2）通过使用钙离子载体A23187（1um/L）快速增加胞内钙离子浓度来探讨胞内钙离子在醛固酮调控快速调控ENaC过程中的作用。
（3）通过使用细胞松弛素D(Cyt D)打断细胞骨架F-actin,探讨细胞形态与ENaC功能活性之间的关系。
4．主要的指标及测量方法
（1）细胞形态学观察：扫描离子电导显微镜（SICM）
（2）跨膜电阻值：跨膜电阻仪（EVOM2）
（3）单通道离子电流：膜片钳cell-attached单通道记录
（4）胞内钙离子:高速比率钙离子浓度测量荧光显微技术
结果：
1.建立了具有ENaC活性哺乳动物肾上皮细胞模型-mpkCCD细胞模型。
2.醛固酮作用于mpkCCD细胞，细胞发生横向收缩纵向伸展，胞内钙离子浓度升高，整体膜和单通道水平的ENaC活性增强，表现为阿米洛利敏感的跨膜电阻升高和离子通道开放概率增加。
3. LY294002能够阻断醛固酮对ENaC的激活作用，表现为细胞恢复原貌，阿米洛利敏感的跨膜电阻降低和离子通道开放概率减少。
4. A23187能迅速增加胞内钙离子浓度，并增强ENaC活性，表现在阿米洛利敏感的跨膜电阻升高和离子通道开放概率增加。
5. Cyt D能使细胞发生横向收缩纵向伸展的形变，ENaC活性增强，表现为阿米洛利敏感的跨膜电阻升高和离子通道开放概率增加。
结论：
1.醛固酮能够快速增强ENaC活性。
2.醛固酮快速增强ENaC活性作用机制可能是通过快速增加胞内钙离子浓度，激活PI3-K通路，使细胞发生横向收缩纵向伸展的形变，从而增加的离子通道的开放概率。
3. Cyt D能使细胞发生形变（横向收缩纵向伸展），ENaC活性增强，说明细胞骨架F-actin解聚有利于提高离子通道开放概率。
Object: Aldosterone play an important role in regulation of extracellular volume, electrolyteshomeostasis and blood pressure control. These physical function depend on the limitedregulation of sodium reabsorption by epithelial sodium channel (ENaC) in cortical connectingduct, the mechanisms of ENaC regulation by Aldo is compose of genomic and nongenomicaction in present study. The mechanism of genomic is clear: the Aldo enter the principle cellof cortical connecting duct (CCD) and binding with MR in intracytoplasm, and Aldo-MRcomplex transport into intranuclear and interact with the specific DNA bingding site whichfinally regulate specific mRNA transcripte and synthesis several aldosterone induced protein(AIP). And then AIP increase the ENaC activity hence promote the sodium reabsorption byENaC. An other mechanism is nongenomic ation,the character of nogenomic of Aldo is rapidand non-MR-dependence, but the underlying mechanism is still unclear,. For furtherunderstand the physiology and pathology meaning of ENaC regulation by aldosterone, wewill explore the rapid regulation of aldosterone on ENaC and its possible mechanism.On theother hand,it could help to promote the development of new drugs like aldosteronicantagonist.
Content:
1Establishment and assessment of the mammalian epithelial cell model that have ENaCactivity.
2Research the rapid regulation of ENaC activity by aldosterone.
3Explore the mechanism of the rapid regulation by aldosterone.
Method:
1. Establishment of cell modelWe estabish mammalian renal epithelia cell mode that have ENaC activity. MDCKand mpkCCD were cultured to integrate monolayer which have high resistance and sensitiveto amiloride. Finally, the cell model were assessed by morphologic observation, TEERmeasurement and sigle channel recording and the better one were selected for furtherresearch.
2. Rapid regulation by aldosterone
MR blocker-aldactone were added to Verify the non-MR-depended rapid regulation(＜ 3hours).after addition of10-6M/L aldosterone on mpkCCD monolayer, toppgraphic imagewere observed, amiloride-sensitive△TEER were measured,single channel current wererecorded and intracellular calcium concentration were detected.
3. The mechanism of rapid ENaC regulation by aldosterone
（1） The specific PI3-K blocker were used to identify the function of PI3-K pathway inrapid regulation on ENaC by aldosterone.
（2） Cacium loader A23187were used to increase the concentration of intracellularcalcium and explore the effect of intracellular calcium change on rapid regulation on ENaCby aldosterone.
（3） Cyt D were used to disrupt the F-acin of cystoskeleton and discuss the relationship ofcell morphology and EaNC activity.
4. Main index and measurement
（1） Morphology observation: SICM
（2） TEER: EVOM2
（3） Single channel recording: patch clamp cell-attached configuration
Result:
1. Establish mpkCCD mammalian epithelia cell model that have EaNC activity.
2. After addition of aldosteron, cell transversal contract and ongitudinal stretching, EaNCactivity increase both in monolayer and single channel and display amiloride-sensitive△TEER and channel open probability improve.
3. LY294002block the increase of aldosterone induced EaNC activity and recover thetopographic change,decrese the miloride-sensitive△TEER and channel open probability.
4. A23187rapid increase the intracellular calcium concentration and increaseamiloride-sensitive△TEER and channel open probability.
5. Cyt D make the cell transversal contract and longitudinal stretching and increaseamiloride-sensitive△TEER and channel open probability.
Conclusion:
1. Aldosterone rapid increase the EaNC activity.
2. PI3-K pathway and cacium play an important role in aldosterone rapid increase EaNCactivity.
3. Morphological change (transversal contract and longitudinal stretching) increase EaNCactivity reveal that morphology and EaNC activity close relative.
主要内容：
1建立具有ENaC活性的哺乳动物肾上皮细胞模型并进行评价。
2研究醛固酮快速调控ENaC的作用。
3探讨醛固酮快速调控ENaC的可能机制。
研究方法：
1．实验细胞模型的建立
建立具有ENaC活性的哺乳动物肾上皮细胞模型-选择MDCK（Madin-Darbycanine kidney）、mpkCCD（mouse principle cell of kidney in cortical collecting duct）两种细胞株，培养成具有完整膜，有极性，高阻抗，阿米洛利敏感的细胞模型,最后通过观察细胞形态结构、测量跨膜电阻值、测量细胞单通道记录三个方面来评估，择优选出适合进一步实验的理想细胞模型。
2．醛固酮对ENaC的快速调控作用
给予醛固酮(10-6M/L)作用于mpkCCD细胞模型，观察醛固酮对细胞形态结构、阿米洛利敏感的跨膜电阻、胞内钙离子浓度、单通道离子电流的影响。使用MR阻断剂螺内酯以及醛固酮转录、蛋白合成抑制剂，验证醛固酮对ENaC快速（＜3小时）调节作用主要是非依赖MR的非基因组作用。
3．醛固酮对ENaC作用机制的研究
（1）通过使用PI3-K通路特异性的阻断剂LY294002(50um/L)验证PI3-K通路在醛固酮快速调控ENaC过程中的作用。
（2）通过使用钙离子载体A23187（1um/L）快速增加胞内钙离子浓度来探讨胞内钙离子在醛固酮调控快速调控ENaC过程中的作用。
（3）通过使用细胞松弛素D(Cyt D)打断细胞骨架F-actin,探讨细胞形态与ENaC功能活性之间的关系。
4．主要的指标及测量方法
（1）细胞形态学观察：扫描离子电导显微镜（SICM）
（2）跨膜电阻值：跨膜电阻仪（EVOM2）
（3）单通道离子电流：膜片钳cell-attached单通道记录
（4）胞内钙离子:高速比率钙离子浓度测量荧光显微技术
结果：
1.建立了具有ENaC活性哺乳动物肾上皮细胞模型-mpkCCD细胞模型。
2.醛固酮作用于mpkCCD细胞，细胞发生横向收缩纵向伸展，胞内钙离子浓度升高，整体膜和单通道水平的ENaC活性增强，表现为阿米洛利敏感的跨膜电阻升高和离子通道开放概率增加。
3. LY294002能够阻断醛固酮对ENaC的激活作用，表现为细胞恢复原貌，阿米洛利敏感的跨膜电阻降低和离子通道开放概率减少。
4. A23187能迅速增加胞内钙离子浓度，并增强ENaC活性，表现在阿米洛利敏感的跨膜电阻升高和离子通道开放概率增加。
5. Cyt D能使细胞发生横向收缩纵向伸展的形变，ENaC活性增强，表现为阿米洛利敏感的跨膜电阻升高和离子通道开放概率增加。
结论：
1.醛固酮能够快速增强ENaC活性。
2.醛固酮快速增强ENaC活性作用机制可能是通过快速增加胞内钙离子浓度，激活PI3-K通路，使细胞发生横向收缩纵向伸展的形变，从而增加的离子通道的开放概率。
3. Cyt D能使细胞发生形变（横向收缩纵向伸展），ENaC活性增强，说明细胞骨架F-actin解聚有利于提高离子通道开放概率。
Object: Aldosterone play an important role in regulation of extracellular volume, electrolyteshomeostasis and blood pressure control. These physical function depend on the limitedregulation of sodium reabsorption by epithelial sodium channel (ENaC) in cortical connectingduct, the mechanisms of ENaC regulation by Aldo is compose of genomic and nongenomicaction in present study. The mechanism of genomic is clear: the Aldo enter the principle cellof cortical connecting duct (CCD) and binding with MR in intracytoplasm, and Aldo-MRcomplex transport into intranuclear and interact with the specific DNA bingding site whichfinally regulate specific mRNA transcripte and synthesis several aldosterone induced protein(AIP). And then AIP increase the ENaC activity hence promote the sodium reabsorption byENaC. An other mechanism is nongenomic ation,the character of nogenomic of Aldo is rapidand non-MR-dependence, but the underlying mechanism is still unclear,. For furtherunderstand the physiology and pathology meaning of ENaC regulation by aldosterone, wewill explore the rapid regulation of aldosterone on ENaC and its possible mechanism.On theother hand,it could help to promote the development of new drugs like aldosteronicantagonist.
Content:
1Establishment and assessment of the mammalian epithelial cell model that have ENaCactivity.
2Research the rapid regulation of ENaC activity by aldosterone.
3Explore the mechanism of the rapid regulation by aldosterone.
Method:
1. Establishment of cell modelWe estabish mammalian renal epithelia cell mode that have ENaC activity. MDCKand mpkCCD were cultured to integrate monolayer which have high resistance and sensitiveto amiloride. Finally, the cell model were assessed by morphologic observation, TEERmeasurement and sigle channel recording and the better one were selected for furtherresearch.
2. Rapid regulation by aldosterone
MR blocker-aldactone were added to Verify the non-MR-depended rapid regulation(＜ 3hours).after addition of10-6M/L aldosterone on mpkCCD monolayer, toppgraphic imagewere observed, amiloride-sensitive△TEER were measured,single channel current wererecorded and intracellular calcium concentration were detected.
3. The mechanism of rapid ENaC regulation by aldosterone
（1） The specific PI3-K blocker were used to identify the function of PI3-K pathway inrapid regulation on ENaC by aldosterone.
（2） Cacium loader A23187were used to increase the concentration of intracellularcalcium and explore the effect of intracellular calcium change on rapid regulation on ENaCby aldosterone.
（3） Cyt D were used to disrupt the F-acin of cystoskeleton and discuss the relationship ofcell morphology and EaNC activity.
4. Main index and measurement
（1） Morphology observation: SICM
（2） TEER: EVOM2
（3） Single channel recording: patch clamp cell-attached configuration
Result:
1. Establish mpkCCD mammalian epithelia cell model that have EaNC activity.
2. After addition of aldosteron, cell transversal contract and ongitudinal stretching, EaNCactivity increase both in monolayer and single channel and display amiloride-sensitive△TEER and channel open probability improve.
3. LY294002block the increase of aldosterone induced EaNC activity and recover thetopographic change,decrese the miloride-sensitive△TEER and channel open probability.
4. A23187rapid increase the intracellular calcium concentration and increaseamiloride-sensitive△TEER and channel open probability.
5. Cyt D make the cell transversal contract and longitudinal stretching and increaseamiloride-sensitive△TEER and channel open probability.
Conclusion:
1. Aldosterone rapid increase the EaNC activity.
2. PI3-K pathway and cacium play an important role in aldosterone rapid increase EaNCactivity.
3. Morphological change (transversal contract and longitudinal stretching) increase EaNCactivity reveal that morphology and EaNC activity close relative.
引文
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46Barter MJ, Pybus L, Litherland GJ, Rowan AD, Clark IM, Edwards DR, etal. HDAC-mediated control of ERK-and PI3K-dependent TGF-beta-inducedextracellular matrix-regulating genes. Matrix Biol2010,29:602-612.
47Nowicki TS, Zhao H, Darzynkiewicz Z, Moscatello A, Shin E, Schantz S,et al. Downregulation of uPAR inhibits migration, invasion, proliferation,FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinomacells. Cell Cycle2011,10:100-107.
48Kim DE, Min KJ, Kim JS, Kwon TK. High-mobility group box-1proteininduces mucin8expression through the activation of the JNK and PI3K/Akt signalpathways in human airway epithelial cells. Biochem Biophys Res Commun2012,421:436-441.
49Zheng L, Ren JQ, Chen Q, Zhang HP, Zhu HG.[The effect of HER2/neuoverexpression on p53gene expression, cell proliferation and sensitivity togamma-irradiation via the PI3K/Akt pathway in breast cancer cell MCF7].Zhonghua Zhong Liu Za Zhi2004,26:594-597.
50Liu D, Huang Y, Zeng J, Chen B, Huang N, Guo N, et al. Down-regulationof JAK1by RNA interference inhibits growth of the lung cancer cell line A549andinterferes with the PI3K/mTOR pathway. J Cancer Res Clin Oncol2011,137:1629-1640.
51Gorelik J, Zhang Y, Shevchuk AI, Frolenkov GI, Sanchez D, Lab MJ, et al.The use of scanning ion conductance microscopy to image A6cells. Mol CellEndocrinol2004,217:101-108.
52Zhang Y, Gorelik J, Sanchez D, Shevchuk A, Lab M, Vodyanoy I, et al.Scanning ion conductance microscopy reveals how a functional renal epithelialmonolayer maintains its integrity. Kidney Int2005,68:1071-1077.
53Gu Y. Effect of [Cl]i on ENaC activity from mouse cortical collectingduct cells. Journal of Cellular Physiology2008,216:453-457.
54Galizia L, Ojea A, Kotsias BA.[Amiloride sensitive sodium channels(ENaC) and their regulation by proteases]. Medicina (B Aires)2011,71:179-182.
55Pochynyuk O, Bugaj V, Stockand JD. Physiologic regulation of theepithelial sodium channel by phosphatidylinositides. Curr Opin Nephrol Hypertens2008,17:533-540.
56Zhou ZH, Bubien JK. Nongenomic regulation of ENaC by aldosterone.Am J Physiol Cell Physiol2001,281:C1118-1130.
57Dooley R, Harvey BJ, Thomas W. Non-genomic actions of aldosterone:From receptors and signals to membrane targets. Molecular and CellularEndocrinology2012,350:223-234.
58Isenovic E, Muniyappa R, Milivojevic N, Rao Y, Sowers JR. Role ofPI3-kinase in isoproterenol and IGF-1induced ecNOS activity. Biochem BiophysRes Commun2001,285:954-958.
59Alvarez de la Rosa D, Canessa CM. Role of SGK in hormonal regulationof epithelial sodium channel in A6cells. Am J Physiol Cell Physiol2003,284:C404-414.
60Bhargava A, Pearce D. Mechanisms of mineralocorticoid action:determinants of receptor specificity and actions of regulated gene products. TrendsEndocrinol Metab2004,15:147-153.
61Yu L, Helms MN, Yue Q, Eaton DC. Single-channel analysis of functionalepithelial sodium channel (ENaC) stability at the apical membrane of A6distalkidney cells. Am J Physiol Renal Physiol2008,295:F1519-1527.
62Schild L. The epithelial sodium channel and the control of sodium balance.Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease2010,1802:1159-1165.
63Alvarez de la Rosa D, Canessa CM. Role of SGK in hormonal regulation ofepithelial sodium channel in A6cells. Am J Physiol Cell Physiol2003,284:C404-414.
64Malik B, Yue Q, Yue G, Chen XJ, Price SR, Mitch WE, et al. Role ofNedd4-2and polyubiquitination in epithelial sodium channel degradation inuntransfected renal A6cells expressing endogenous ENaC subunits. Am J PhysiolRenal Physiol2005,289:F107-116.
65Himpens B, Vereecke J.[Intra-and intercellular Ca(2+)-signaltransduction]. Verh K Acad Geneeskd Belg2000,62:501-563.
66Hours MC, Mery L. The N-terminal domain of the type1Ins(1,4,5)P3receptor stably expressed in MDCK cells interacts with myosin IIA and altersepithelial cell morphology. J Cell Sci2010,123:1449-1459.
67Ning Z, Li Y, Zhang R.[Effects of methyl protodioscin on [Ca2+]i and ATPaseactivity in cardiomyocytes and analysis of mechanisms]. Zhongguo Zhong Yao ZaZhi2010,35:80-83.
68Kortenoeven ML, van den Brand M, Wetzels JF, Deen PM.Hypotonicity-induced reduction of aquaporin-2transcription in mpkCCD cells isindependent of the tonicity responsive element, vasopressin, and cAMP. J Biol Chem2011,286:13002-13010.
69Cantiello HF. Role of the actin cytoskeleton on epithelial Na+channelregulation. Kidney Int1995,48:970-984.
70Rameh LE, Rhee SG, Spokes K, Kazlauskas A, Cantley LC, Cantley LG.Phosphoinositide3-kinase regulates phospholipase Cgamma-mediated calciumsignaling. J Biol Chem1998,273:23750-23757.
71Pochynyuk O, Bugaj V, Stockand JD. Physiologic regulation of theepithelial sodium channel by phosphatidylinositides. Curr Opin Nephrol Hypertens2008,17:533-540.
72Butterworth MB. Regulation of the epithelial sodium channel (ENaC) bymembrane trafficking. Biochim Biophys Acta2010,1802:1166-1177.
73Yu L, Helms MN, Yue Q, Eaton DC. Single-channel analysis of functionalepithelial sodium channel (ENaC) stability at the apical membrane of A6distalkidney cells. Am J Physiol Renal Physiol2008,295:F1519-1527.
74Pratt JH. Central role for ENaC in development of hypertension. J Am SocNephrol2005,16:3154-3159.
75Wiemuth D, Ke Y, Rohlfs M, McDonald FJ. Epithelial sodium channel (ENaC)is multi-ubiquitinated at the cell surface. Biochem J2007,405:147-155.
76Wehling M. Specific, nongenomic actions of steroid hormones. Annu RevPhysiol1997,59:365-393.
77May A, Puoti A, Gaeggeler HP, Horisberger JD, Rossier BC. Early effectof aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunitin A6renal cells. J Am Soc Nephrol1997,8:1813-1822.
78Zhou ZH, Bubien JK. Nongenomic regulation of ENaC by aldosterone.Am J Physiol Cell Physiol2001,281:C1118-1130.
79Ma HP, Chou CF, Wei SP, Eaton DC. Regulation of the epithelial sodiumchannel by phosphatidylinositides: experiments, implications, and speculatio ns.Pflugers Arch2007,455:169-180.
80Zhang Y DS, Julia Gorelik, David Klenerman,, Max Lab CE, and Yuri Korchev.Basolateral P2X4-like receptors regulate the extracellular ATP-stimulated
81epithelial Na+channel activity in renal epithelia. Am J Physiol Renal Physiol2007,292:1734-1740.
82Zhang Y, Sanchez D, Gorelik J, Klenerman D, Lab M, Edwards C, et al.Basolateral P2X4-like receptors regulate the extracellular ATP-stimulated epithelialNa+channel activity in renal epithelia. Am J Physiol Renal Physiol2007,292:F1734-1740.
83Staruschenko A, Pochynyuk O, Vandewalle A, Bugaj V, Stockand JD. AcuteRegulation of the Epithelial Na+Channel by Phosphatidylinositide3-OH KinaseSignaling in Native Collecting Duct Principal Cells. Journal of the American Societyof Nephrology2007,18:1652-1661.
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3Thomas W, McEneaney V, Harvey B. Aldosterone-induced signalling andcation transport in the distal nephron. Steroids2008,73:979-984.
4Garty H, Palmer LG. Epithelial sodium channels: function, structure, andregulation. Physiol Rev1997,77:359-396.
5Alvarez de la Rosa D, Canessa CM, Fyfe GK, Zhang P. Structure andregulation of amiloride-sensitive sodium channels. Annu Rev Physiol2000,62:573-594.
6Pratt JH. Central role for ENaC in development of hypertension. J Am SocNephrol2005,16:3154-3159.
7Dooley R, Harvey BJ, Thomas W. Non-genomic actions of aldosterone:From receptors and signals to membrane targets. Molecular and CellularEndocrinology2011.
8Lu C, Pribanic S, Debonneville A, Jiang C, Rotin D. The PY moti f ofENaC, mutated in Liddle syndrome, regulates channel internalization, sorting andmobilization from subapical pool. Traffic2007,8:1246-1264.
9Kamynina E, Debonneville C, Hirt RP, Staub O. Liddle's syndrome: anovel mouse Nedd4isoform regulates the activity of the epithelial Na(+) channel.Kidney Int2001,60:466-471.
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19May A, Puoti A, Gaeggeler HP, Horisberger JD, Rossier BC. Early effectof aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunitin A6renal cells. J Am Soc Nephrol1997,8:1813-1822.
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26Cantiello HF. Role of the actin cytoskeleton on epithelial Na+channelregulation. Kidney Int1995,48:970-984.
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34Pratt JH. Central role for ENaC in development of hypertension. J Am SocNephrol2005,16:3154-3159.
35Rossi E, Farnetti E, Nicoli D, Sazzini M, Perazzoli F, Regolisti G, et al. Aclinical phenotype mimicking essential hypertension in a newly discovered familywith Liddle's syndrome. Am J Hypertens2011,24:930-935.
36Kemendy AE, Kleyman TR, Eaton DC. Aldosterone alters the openprobability of amiloride-blockable sodium channels in A6epithelia. Am J Physiol1992,263:C825-837.
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45Weisberg E, Banerji L, Wright RD, Barrett R, Ray A, Moreno D, et al.Potentiation of antileukemic therapies by the dual PI3K/PDK-1inhibitor, BAG956:effects on BCR-ABL-and mutant FLT3-expressing cells. Blood2008,111:3723-3734.
46Barter MJ, Pybus L, Litherland GJ, Rowan AD, Clark IM, Edwards DR, etal. HDAC-mediated control of ERK-and PI3K-dependent TGF-beta-inducedextracellular matrix-regulating genes. Matrix Biol2010,29:602-612.
47Nowicki TS, Zhao H, Darzynkiewicz Z, Moscatello A, Shin E, Schantz S,et al. Downregulation of uPAR inhibits migration, invasion, proliferation,FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinomacells. Cell Cycle2011,10:100-107.
48Kim DE, Min KJ, Kim JS, Kwon TK. High-mobility group box-1proteininduces mucin8expression through the activation of the JNK and PI3K/Akt signalpathways in human airway epithelial cells. Biochem Biophys Res Commun2012,421:436-441.
49Zheng L, Ren JQ, Chen Q, Zhang HP, Zhu HG.[The effect of HER2/neuoverexpression on p53gene expression, cell proliferation and sensitivity togamma-irradiation via the PI3K/Akt pathway in breast cancer cell MCF7].Zhonghua Zhong Liu Za Zhi2004,26:594-597.
50Liu D, Huang Y, Zeng J, Chen B, Huang N, Guo N, et al. Down-regulationof JAK1by RNA interference inhibits growth of the lung cancer cell line A549andinterferes with the PI3K/mTOR pathway. J Cancer Res Clin Oncol2011,137:1629-1640.
51Gorelik J, Zhang Y, Shevchuk AI, Frolenkov GI, Sanchez D, Lab MJ, et al.The use of scanning ion conductance microscopy to image A6cells. Mol CellEndocrinol2004,217:101-108.
52Zhang Y, Gorelik J, Sanchez D, Shevchuk A, Lab M, Vodyanoy I, et al.Scanning ion conductance microscopy reveals how a functional renal epithelialmonolayer maintains its integrity. Kidney Int2005,68:1071-1077.
53Gu Y. Effect of [Cl]i on ENaC activity from mouse cortical collectingduct cells. Journal of Cellular Physiology2008,216:453-457.
54Galizia L, Ojea A, Kotsias BA.[Amiloride sensitive sodium channels(ENaC) and their regulation by proteases]. Medicina (B Aires)2011,71:179-182.
55Pochynyuk O, Bugaj V, Stockand JD. Physiologic regulation of theepithelial sodium channel by phosphatidylinositides. Curr Opin Nephrol Hypertens2008,17:533-540.
56Zhou ZH, Bubien JK. Nongenomic regulation of ENaC by aldosterone.Am J Physiol Cell Physiol2001,281:C1118-1130.
57Dooley R, Harvey BJ, Thomas W. Non-genomic actions of aldosterone:From receptors and signals to membrane targets. Molecular and CellularEndocrinology2012,350:223-234.
58Isenovic E, Muniyappa R, Milivojevic N, Rao Y, Sowers JR. Role ofPI3-kinase in isoproterenol and IGF-1induced ecNOS activity. Biochem BiophysRes Commun2001,285:954-958.
59Alvarez de la Rosa D, Canessa CM. Role of SGK in hormonal regulationof epithelial sodium channel in A6cells. Am J Physiol Cell Physiol2003,284:C404-414.
60Bhargava A, Pearce D. Mechanisms of mineralocorticoid action:determinants of receptor specificity and actions of regulated gene products. TrendsEndocrinol Metab2004,15:147-153.
61Yu L, Helms MN, Yue Q, Eaton DC. Single-channel analysis of functionalepithelial sodium channel (ENaC) stability at the apical membrane of A6distalkidney cells. Am J Physiol Renal Physiol2008,295:F1519-1527.
62Schild L. The epithelial sodium channel and the control of sodium balance.Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease2010,1802:1159-1165.
63Alvarez de la Rosa D, Canessa CM. Role of SGK in hormonal regulation ofepithelial sodium channel in A6cells. Am J Physiol Cell Physiol2003,284:C404-414.
64Malik B, Yue Q, Yue G, Chen XJ, Price SR, Mitch WE, et al. Role ofNedd4-2and polyubiquitination in epithelial sodium channel degradation inuntransfected renal A6cells expressing endogenous ENaC subunits. Am J PhysiolRenal Physiol2005,289:F107-116.
65Himpens B, Vereecke J.[Intra-and intercellular Ca(2+)-signaltransduction]. Verh K Acad Geneeskd Belg2000,62:501-563.
66Hours MC, Mery L. The N-terminal domain of the type1Ins(1,4,5)P3receptor stably expressed in MDCK cells interacts with myosin IIA and altersepithelial cell morphology. J Cell Sci2010,123:1449-1459.
67Ning Z, Li Y, Zhang R.[Effects of methyl protodioscin on [Ca2+]i and ATPaseactivity in cardiomyocytes and analysis of mechanisms]. Zhongguo Zhong Yao ZaZhi2010,35:80-83.
68Kortenoeven ML, van den Brand M, Wetzels JF, Deen PM.Hypotonicity-induced reduction of aquaporin-2transcription in mpkCCD cells isindependent of the tonicity responsive element, vasopressin, and cAMP. J Biol Chem2011,286:13002-13010.
69Cantiello HF. Role of the actin cytoskeleton on epithelial Na+channelregulation. Kidney Int1995,48:970-984.
70Rameh LE, Rhee SG, Spokes K, Kazlauskas A, Cantley LC, Cantley LG.Phosphoinositide3-kinase regulates phospholipase Cgamma-mediated calciumsignaling. J Biol Chem1998,273:23750-23757.
71Pochynyuk O, Bugaj V, Stockand JD. Physiologic regulation of theepithelial sodium channel by phosphatidylinositides. Curr Opin Nephrol Hypertens2008,17:533-540.
72Butterworth MB. Regulation of the epithelial sodium channel (ENaC) bymembrane trafficking. Biochim Biophys Acta2010,1802:1166-1177.
73Yu L, Helms MN, Yue Q, Eaton DC. Single-channel analysis of functionalepithelial sodium channel (ENaC) stability at the apical membrane of A6distalkidney cells. Am J Physiol Renal Physiol2008,295:F1519-1527.
74Pratt JH. Central role for ENaC in development of hypertension. J Am SocNephrol2005,16:3154-3159.
75Wiemuth D, Ke Y, Rohlfs M, McDonald FJ. Epithelial sodium channel (ENaC)is multi-ubiquitinated at the cell surface. Biochem J2007,405:147-155.
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