臺灣博碩士論文加值系統

前言
細胞內 pH (pHi) 值會去影響細胞內的許多功能。目前已知在哺乳動物細胞上的 pHi 調控蛋白有 Na+/H+ 交換蛋白 (NHE)、 Na+/HCO3- 共同交換蛋白 (NHS)、 Lactate-/H+ symporter (LHS)、 Cl-/OH- 交換蛋白 (CHE)、 Cl-/HCO3- 交換蛋白 (AE) 。腹膜透析是治療慢性尿毒症病人的其中一種方法，目前臨床四種腹膜透析液 (peritoneal dialysis fluids, PDFs) ： Dianeal、 Extraneal、 Nutrineal 和 Physioneal 各有其不同 pH (5.2, 5.2, 6.3 and 7.4) 。

實驗目的
利用人類腹膜間皮細胞 (human peritoneal mesothelial cells, HPMCs) : (1.) 證明是否存在著排酸蛋白 NHE 及 NHS 並同時觀察 NHE 及 NHS 於排酸機轉上的互動，和 NHE 分型; (2.) 探討不同 PDFs 及不同 pHo 溶液對於 pHi 的影響; (3.) 探討LHS 生理上功能性的表現，並比較不同 pHo 環境對於 HPMCs 上的 LHS 活性影響。

實驗材料與方法
1.直接利用人類腹膜組織培養 HPMCs ，並用細胞免疫染色法鑑定。
2.測量細胞 pHi 是利用顯微螢光技術將細胞載入 BCECF-AM 後，記錄激發光波長所激發之螢光強度比值 (R490/440) ，來代表 pHi 的變化。
3.利用細胞/組織免疫染色法分別去確定腹膜組織切片及 HPMCs 上 NHE-1、 NHE-2 及 NHE-3 的存在。

結果
1.成功地利用腹膜組織培養出 HPMCs 及建立一個例行性的培養模式。
2.在 HEPES 緩衝溶液下，當移除細胞外鈉離子或是單獨給予 HOE 694 (NHE 專一性抑制劑) 情況下，可以完全抑制 NH4Cl 所引起的排酸斜率，證實 NHE 的存在。
3.在 bicarbonate 緩衝溶液下，當給予 HOE 694 或 DIDS (NHS 專一性抑制劑) ，可以部份抑制 NH4Cl 所引起的排酸斜率；而當移除細胞外鈉離子或 HOE 694 與 DIDS 同時加入情況下，可以全部抑制排酸斜率，證實 NHS 的存在。
4.在 HEPES 或 bicarbonate 緩衝溶液下， 4 種不同 PDFs (分別是 pH 5.2, 5.2, 6.3, 8.0) ，都會明顯依賴 PDFs pH 值不同而改變 HPMCs pHi 。
5.在 HEPES 或 bicarbonate 緩衝溶液下，我們證明灌流不同 pHo溶液 (5.2~8.0) 對 HPMCs pHi 之影響皆為一線性正向依賴變化之關係。
6.在 sodium citrate 溶液下，當給予 CHC (LHS 抑制劑) ，可以抑制 lactate 所引起的排酸斜率，證實 LHS 的存在。而 lactate 所引起的排酸動力學並不會受到 HOE 694 或 40 mM lactate 甚至是 bicarbonate 或 HEPES 緩衝溶液的影響。

結論
1.我們首次證明至少存在著兩個與 Na+ 相關的排酸機轉 (NHE, NHS 穿膜運輸蛋白) 和 LHS 功能性地存在在人類腹膜間皮細胞膜上，且 HPMCs 細胞膜上有 NHE-1/-3 的存在。
2.臨床上常用的腹膜透析液對於 HPMCs pHi 的影響非常巨大，所以改善腹膜透析液對腹膜透析的療效影響是值得進一步研究的。
3.我們證明 pHi 對於pHo 有一線性正向依賴變化之關係， HPMCs 本身對酸的衝擊緩衝能力比對鹼的衝擊緩衝能力好，且在 bicarbonate 溶液情況下的緩衝能力比在 HEPES 溶液情況下大。 bicarbonate 溶液(pH 5.2~7.4) 是 HPMCs 最好的緩衝溶液。

Introduction
Intracellular pH (pHi) changes were found to influence many cellular functions. To date, the pHi regulators include Na+/H+ exchanger (NHE), Na+/HCO3- symporter (NHS), lactate-/H+ symporter (LHS), Cl-/OH- exchanger (CHE) and Cl-/HCO3- exchanger (AE) in the mammalian cells. Then, peritoneal dialysis (PD) is one method of treating chronic uremic patients. Available 4 commercial peritoneal dialysis fluids (PDFs), Dianeal, Extraneal, Nutrineal and Physioneal, have various but dramatic different on pH values (pH is 5.2, 5.2, 6.3 and 7.4 respectively).

Objects
The aims of the study used the human peritoneal mesothelial cells (HPMCs) to: (1.) investigate the underlying mechanisms for its effects on pHi regulation (NHE and NHS) and NHE isoforms; (2.) explore the effects of commercial PDFs and different pHo solutions on pHi; (3.) investigate the LHS, the effects of 40 mM lactate and different buffered solutions on LHS activity.

Materials and Methods
1.HPMCs were cultured directly from peritoneal tissue and identified by immunocytochemistry.
2.The measurement of pHi was detected by microspectrofluorimetry method with BCECF-AM. We recorded fluorescence ratio (R490/440), which represented the change of pHi.
3.Immunocyto/histochemistry were used to identify NHE-1, NHE-2 and NHE-3 in HPMCs or peritoneal biopsy tissues.

Results
1.We have successfully cultured human peritoneal mesothelial primary cells from tissue and set-up a reproduceable model for routine use.
2.In HEPES-buffered solution, removal of extracellular Na+ or adding HOE 694 (a specific NHE inhibitor) alone can totally inhibit the recovery from NH4Cl-induced intracellular acidosis, which prove the existence of NHE.
3.In bicarbonate-buffered solution, either HOE 694 or DIDS (a specific NHS inhibitor) alone only partially inhibited the recovery from NH4Cl-induced intracellular acidosis, while removal of Na+ or adding together HOE 694 and DIDS totally inhibited the recovery. This demonstrate the existence of NHS.
4.Both in HEPES- and bicarbonate-buffered solution, all 4 different PDFs (pH 5.2, 5.2, 6.3, 7.4, respectively) significantly changed HPMCs pHi.
5.Both in HEPES- and bicarbonate-buffered solution, we demonstrated that, in the HPMCs, pHi is increased linearly as pHo rising from 5.2 to 8.0.
6.In sodium citrate solution, CHC (a LHS inhibitor) inhibited pHi recovery from lactate-induced intracellular acidosis, which proves the existence of LHS. Lactate-induced intracellular acidosis kinetice was not affected by HOE 694 or 40 mM lactate, either in bicarbonate- or HEPES-buffered solutions.

Conclusions
1.We have demonstrated for the first time that, two Na+-dependent acid-extruders (NHE and NHS) and LHS are functionally existed in the HPMCs. NHE-1 and NHE-3 were identified in HPMCs.
2.Commercial PDFs used in clinics significantly affect HPMCs pHi, which suggest the space for the improvement or developing new PDFs.
3.We have demonstrated that pHi is functional linearly as pHo. In bicarbonate- buffered solution (pH 5.2~7.4), it was best buffered solution for HPMCs.

正文目錄
頁次
正文目錄------------------------------------------------------------------------------------I
表目錄-------------------------------------------------------------------------------------VI
圖目錄------------------------------------------------------------------------------------VII
中文摘要----------------------------------------------------------------------------------X
英文摘要---------------------------------------------------------------------------------XII

第一章 序論----------------------------------------------------------------1
第一節 腎衰竭-------------------------------------------------------------1
壹、 腎臟-------------------------------------------------------------------2
貳、 腎衰竭----------------------------------------------------------------4
參、 腎衰竭的治療方式-------------------------------------------------5
第二節 腹膜透析----------------------------------------------------------7
壹、 何謂腹膜透析-------------------------------------------------------7
貳、 腹膜透析的失敗----------------------------------------------------9
參、 臨床上使用的腹膜透析液種類與成份------------------------13
第三節 細胞內 pH 值的調控------------------------------------------16
壹、 主動或被動運輸細胞內氫離子---------------------------------17
貳、 pHi regulator 的證實--------------------------------------------20
參、 排酸蛋白 Na+-H+ exchanger （NHE）--------------------20
肆、 排酸蛋白 Na+-HCO3- symportor （NHS）---------------23
伍、 NHE 及 NHS 於排酸機轉上的互動--------------------------25
第四節 乳酸對腹膜間皮細胞的影響--------------------------------26
壹、 乳酸的生理角色--------------------------------------------------26
貳、 Lactate--H+ symportor （LHS） 運輸動力學------------28

第二章 實驗材料與方法-----------------------------------------------30
第一節 溶液與藥品-----------------------------------------------------30
壹、 細胞培養-----------------------------------------------------------30
一、 Cell medium ----------------------------------------------------30
二、 Others--------------------------------------------------------------30
貳、 實驗溶液-----------------------------------------------------------30
一、 HEPES 緩衝溶液------------------------------------------------30
二、 Bicarbonate緩衝溶液------------------------------------------31
三、 PBS 等張緩衝溶液----------------------------------------------31
四、 Sodium citrate緩衝溶液---------------------------------------31
五、 10 % 福馬林溶液------------------------------------------------32
參、 實驗藥品-----------------------------------------------------------32
一、 BCECF-AM--------------------------------------------------------32
二、 Buffer system----------------------------------------------------32
三、 Other drugs-------------------------------------------------------32
第二節 實驗標本--------------------------------------------------------33
第三節 實驗儀器及裝置-----------------------------------------------33
壹、 實驗標本之架置--------------------------------------------------33
貳、 儀器原理與設備--------------------------------------------------34
第四節 實驗方法--------------------------------------------------------35
壹、 細胞培養-----------------------------------------------------------35
一、 前處理--------------------------------------------------------------35
二、 培養腹膜間皮細胞-----------------------------------------------35
三、 細胞鑑定 (細胞免疫染色法) -----------------------------------36
貳、 細胞免疫染色法--------------------------------------------------36
參、 組織切片免疫染色法--------------------------------------------37
肆、 顯微螢光技術-----------------------------------------------------37
一、 螢光原理-----------------------------------------------------------38
二、 螢光應用-----------------------------------------------------------38
伍、 pHi 校正------------------------------------------------------------40
陸、 NH4Cl pre-pulse 技術------------------------------------------43
柒、 測量 LHS 運輸動力學技術-------------------------------------44
第五節 統計方法---------------------------------------------------------44

第三章 實驗結果--------------------------------------------------------45
第一節 人類腹膜間皮細胞培養及其鑑定--------------------------46
第二節 人類腹膜間皮細胞之主動排酸機轉-----------------------46
壹、 證實主動排酸機轉 NHE 存在---------------------------------47
一、 生理性證明--------------------------------------------------------47
二、 藥理性證明--------------------------------------------------------47
三、 細胞/組織免疫染色法證明-------------------------------------48
貳、 證實主動排酸機轉 NHS 存在---------------------------------48
一、 生理性證明--------------------------------------------------------48
二、 藥理性證明--------------------------------------------------------49
第三節 腹膜透析液於 HEPES-buffererd solution 下，對於人類腹膜間皮細胞 pHi 之影響-----------------------------------------------------51
第四節 腹膜透析液於 HCO3-/CO2-buffered solution 下，對於人類腹膜間皮細胞 pHi 之影響------------------------------------------------51
第五節 HEPES-buffered 灌流溶液下，改變人類腹膜間皮細胞 pHo 對 pHi 之影響--------------------------------------------------------------52
第六節 HCO3-/CO2-buffered 灌流溶液下，改變人類腹膜間皮細胞 pHo 對 pHi 之影響--------------------------------------------------------53
第七節 人類腹膜間皮細胞 lactate-/H+ symportor (LHS) 在生理上功能性的表現------------------------------------------------------------------54
第八節 人類腹膜間皮細胞 lactate-/H+ symporter (LHS) 在不同緩衝溶液中生理上功能性的表現---------------------------------------------55

第四章 討論------------------------------------------------------------------------------------------------------56
第一節 探討人類腹膜間皮細胞之主動排酸機轉---------------------------------------------------------56
第二節 探討腹膜透析液對於人類腹膜間皮細胞 pHi 之影響------------------------------------------57
第三節 pHo 對 pHi 之影響------------------------------------------------------------------------------------60
第四節 人類腹膜間皮細胞 lactate-/H+ symporter (LHS) 在生理上功能性的表現---------------62

第五章 結論--------------------------------------------------------------------------64
參考文獻 (依作者英文字母排列) -----------------------------------------------97


表目錄
表1. 腎臟功能檢查項目及其參考值--------------------------------------------65
表2. 腹膜透析與血液透析的比較-----------------------------------------------66
表3. 四種臨床上使用的腹膜透析液及其組成成份--------------------------67
表4. 哺乳類動物鈉氫交換蛋白的家族分型 (NHE isoforms) ------------68


圖目錄
頁次
圖1-A 台灣地區民國 86 年透析人數統計圖----------------------------------69
圖1-B 台灣地區民國 96 年透析人數統計圖----------------------------------69
圖2 腎臟的基本單位---------------------------------------------------------------70
圖3 執行腹膜透析的順序---------------------------------------------------------71
圖4 腹膜間皮細胞的基本功能---------------------------------------------------72
圖5 天竺鼠心臟細胞 pHi 調控蛋白---------------------------------------------73
圖6 重碳酸根離子排除細胞內酸中毒的機制---------------------------------74
圖7-A 人體肝臟附近的腹膜組織-------------------------------------------------75
圖7-B 人體腹膜組織----------------------------------------------------------------75
圖8 螢光染劑 BCECF 激發光譜圖 ---------------------------------------------76
圖9 載入螢光染劑 BCECF 之原理----------------------------------------------77
圖10 顯微螢光測定法之裝置-----------------------------------------------------78
圖11 螢光強度比值與 pHi 之關係圖--------------------------------------------79
圖12 NH4Cl pre-pulse 誘導細胞內酸化之原理-----------------------------80
圖13 測量 LHS 運輸動力學技術-------------------------------------------------81
圖14 人類腹膜間皮細胞型態及其鑑定-----------------------------------------82
圖15 NHE-1/-2/-3 的細胞免疫染色---------------------------------------------83
圖16 NHE-1/-3 的組織免疫染色-------------------------------------------------84
圖17 在 HEPES 緩衝溶液中，細胞外無鈉環境對人類腹膜間皮細胞排酸能力的影響---------------------------------------------------------------------85
圖18 在 HEPES 緩衝溶液中， HOE 694 對人類腹膜間皮細胞排酸能力的影響----------------------------------------------------------------------------86
圖19 在 HCO3-/CO2 緩衝溶液中，細胞外無鈉環境對人類腹膜間皮細胞排酸能力的影響---------------------------------------------------------------87
圖20 在 HCO3-/CO2 緩衝溶液中， HOE 694 對人類腹膜間皮細胞排酸能力的影響----------------------------------------------------------------------88
圖21 在 HCO3-/CO2 緩衝溶液中， DIDS 對人類腹膜間皮細胞排酸能力的影響---------------------------------------------------------------------------89
圖22 在 HCO3-/CO2 緩衝溶液中， HOE 694+DIDS 對人類腹膜間皮細胞排酸能力的影響-------------------------------------------------------------90
圖23 不同腹膜透析液於 HEPES 緩衝溶液下，對於人類腹膜間皮細胞 pHi 之影響------------------------------------------------------------------------91
圖24 不同腹膜透析液於 HCO3-/CO2 緩衝溶液下，對於人類腹膜間皮細胞 pHi 之影響------------------------------------------------------------------92
圖25 在 HEPES 緩衝溶液中，細胞外 pH 對人類腹膜間皮細胞內 pH 的影響-------------------------------------------------------------------------------93
圖26 在 HCO3-/CO2 緩衝溶液中，細胞外 pH 對人類腹膜間皮細胞內 pH 的影響-------------------------------------------------------------------------94
圖27 給予細胞外 HOE 694、 CHC 和 40 mM lactate ，人類腹膜間皮細胞內 pH 變化-------------------------------------------------------------------95
圖28 在 HCO3-/CO2 及 HEPES緩衝溶液下，對人類腹膜間皮細胞上 LHS 的影響------------------------------------------------------------------------96

Aickin, C. C., 1994. Regulation of intracellular pH in smooth muscle cells of the guinea-pig femoral artery. J Physiol. 479 (Pt 2), 331-340.
Aickin, C. C. and Thomas, R. C., 1977. An investigation of the ionic mechanism of intracellular pH regulation in mouse soleus muscle fibres. J Physiol. 273, 295-316.
Aroeira, L. S., Aguilera, A., Sanchez-Tomero, J. A., Bajo, M. A., del Peso, G., Jimenez-Heffernan, J. A., Selgas, R. and Lopez-Cabrera, M., 2007. Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions. J Am Soc Nephrol. 18, 2004-2013.
Aronson, P. S., Suhm, M. A. and Nee, J., 1983. Interaction of external H+ with the Na+-H+ exchanger in renal microvillus membrane vesicles. J Biol Chem. 258, 6767-6771.
Barrallo-Gimeno, A. and Nieto, M. A., 2005. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 132, 3151-3161.
Betz, A. L., 1983. Sodium transport in capillaries isolated from rat brain. J Neurochem. 41, 1150-1157.
Bonen, A., 2001. The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. Eur J Appl Physiol. 86, 6-11.
Boron, W. F., 2004. Regulation of intracellular pH. Adv Physiol Educ. 28, 160-179.
Boron, W. F. and Boulpaep, E. L., 1983. Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral HCO3- transport. J Gen Physiol. 81, 53-94.
Breborowicz, A., Polubinska, A. and Oreopoulos, D. G., 1999. Changes in volume of peritoneal mesothelial cells exposed to osmotic stress. Perit Dial Int. 19, 119-123.
Brown, C. D., Dunk, C. R. and Turnberg, L. A., 1989. Cl-HCO3 exchange and anion conductance in rat duodenal apical membrane vesicles. Am J Physiol. 257, G661-667.
Cala, P. M., 1983. Cell volume regulation by Amphiuma red blood cells. The role of Ca+2 as a modulator of alkali metal/H+ exchange. J Gen Physiol. 82, 761-784.
Chen, J. C. and Chesler, M., 1992. Extracellular alkaline shifts in rat hippocampal slice are mediated by NMDA and non-NMDA receptors. J Neurophysiol. 68, 342-344.
Collins, J. F., Honda, T., Knobel, S., Bulus, N. M., Conary, J., DuBois, R. and Ghishan, F. K., 1993. Molecular cloning, sequencing, tissue distribution, and functional expression of a Na+/H+ exchanger (NHE-2). Proc Natl Acad Sci U S A. 90, 3938-3942.
Cooker, L. A., Holmes, C. J. and Hoff, C. M., 2002. Biocompatibility of icodextrin. Kidney Int Suppl, S34-45.
Counillon, L. and Pouyssegur, J., 1993. Structure, function, and regulation of vertebrate Na+/H+ exchangers. Curr Opin Nephrol Hypertens. 2, 708-714.
Curci, S., Debellis, L. and Fromter, E., 1987. Evidence for rheogenic sodium bicarbonate cotransport in the basolateral membrane of oxyntic cells of frog gastric fundus. Pflugers Arch. 408, 497-504.
Dart, C. and Vaughan-Jones, R. D., 1992. Na(+)-HCO3- symport in the sheep cardiac Purkinje fibre. J Physiol. 451, 365-385.
Davies, S. J., Phillips, L., Griffiths, A. M., Russell, L. H., Naish, P. F. and Russell, G. I., 1998. What really happens to people on long-term peritoneal dialysis? Kidney Int. 54, 2207-2217.
Dawnay, A. B. and Millar, D. J., 1997. Glycation and advanced glycation end-product formation with icodextrin and dextrose. Perit Dial Int. 17, 52-58.
Denton, R. M. and Halestrap, A. P., 1979. Regulation of pyruvate metabolism in mammalian tissues. Essays Biochem. 15, 37-77.
Dobbie, J. W., 1990. New concepts in molecular biology and ultrastructural pathology of the peritoneum: their significance for peritoneal dialysis. Am J Kidney Dis. 15, 97-109.
Faller, B., Aparicio, M., Faict, D., De Vos, C., de Precigout, V., Larroumet, N., Guiberteau, R., Jones, M. and Peluso, F., 1995. Clinical evaluation of an optimized 1.1% amino-acid solution for peritoneal dialysis. Nephrol Dial Transplant. 10, 1432-1437.
Fenton, S. S., Schaubel, D. E., Desmeules, M., Morrison, H. I., Mao, Y., Copleston, P., Jeffery, J. R. and Kjellstrand, C. M., 1997. Hemodialysis versus peritoneal dialysis: a comparison of adjusted mortality rates. Am J Kidney Dis. 30, 334-342.
Feriani, M., Biasioli, S., Borin, D., Bragantini, L., Brendolan, A., Chiaramonte, S., Dell'Aquila, R., Fabris, A., Ronco, C. and La Greca, G., 1985. Bicarbonate buffer for CAPD solution. Trans Am Soc Artif Intern Organs. 31, 668-672.
Gandhi, V. C., Humayun, H. M., Ing, T. S., Daugirdas, J. T., Jablokow, V. R., Iwatsuki, S., Geis, W. P. and Hano, J. E., 1980. Sclerotic thickening of the peritoneal membrane in maintenance peritoneal dialysis patients. Arch Intern Med. 140, 1201-1203.
Gokal, R., Alexander, S., Ash, S., Chen, T. W., Danielson, A., Holmes, C., Joffe, P., Moncrief, J., Nichols, K., Piraino, B., Prowant, B., Slingeneyer, A., Stegmayr, B., Twardowski, Z. and Vas, S., 1998. Peritoneal catheters and exit-site practices toward optimum peritoneal access: 1998 update. (Official report from the International Society for Peritoneal Dialysis). Perit Dial Int. 18, 11-33.
Grinstein, S., Rotin, D. and Mason, M. J., 1989. Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. Biochim Biophys Acta. 988, 73-97.
Halestrap, A. P., Scott, R. D. and Thomas, A. P., 1980. Mitochondrial pyruvate transport and its hormonal regulation. Int J Biochem. 11, 97-105.
Harguindey, S., Orive, G., Luis Pedraz, J., Paradiso, A. and Reshkin, S. J., 2005. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin--one single nature. Biochim Biophys Acta. 1756, 1-24.
Heimburger, O., Waniewski, J., Werynski, A., Tranaeus, A. and Lindholm, B., 1990. Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney Int. 38, 495-506.
Henderson, R. M., Bell, P. B., Cohen, R. D., Browning, C. and Iles, R. A., 1986. Measurement of intracellular pH with microelectrodes in rat kidney in vivo. Am J Physiol. 250, F203-209.
Holmes, C. J. and Shockley, T. R., 2000. Strategies to reduce glucose exposure in peritoneal dialysis patients. Perit Dial Int. 20 Suppl 2, S37-41.
Jentsch, T. J., Keller, S. K., Koch, M. and Wiederholt, M., 1984. Evidence for coupled transport of bicarbonate and sodium in cultured bovine corneal endothelial cells. J Membr Biol. 81, 189-204.
Johnson, J. D. and Epel, D., 1976. Intracellular pH and activation of sea urchin eggs after fertilisation. Nature. 262, 661-664.
Jones, M., Hagen, T., Boyle, C. A., Vonesh, E., Hamburger, R., Charytan, C., Sandroni, S., Bernard, D., Piraino, B., Schreiber, M., Gehr, T., Fein, P., Friedlander, M., Burkart, J., Ross, D., Zimmerman, S., Swartz, R., Knight, T., Kraus, A., Jr., McDonald, L., Hartnett, M., Weaver, M., Martis, L. and Moran, J., 1998. Treatment of malnutrition with 1.1% amino acid peritoneal dialysis solution: results of a multicenter outpatient study. Am J Kidney Dis. 32, 761-769.
Jorres, A., Gahl, G. M. and Frei, U., 1995. In vitro studies on the effect of dialysis solutions on peritoneal leukocytes. Perit Dial Int. 15, S41-45; discussion S45-46.
Keizer, H. G. and Joenje, H., 1989. Increased cytosolic pH in multidrug-resistant human lung tumor cells: effect of verapamil. J Natl Cancer Inst. 81, 706-709.
Kettenmann, H. and Schlue, W. R., 1988. Intracellular pH regulation in cultured mouse oligodendrocytes. J Physiol. 406, 147-162.
Kinsella, J. L. and Aronson, P. S., 1980. Properties of the Na+-H+ exchanger in renal microvillus membrane vesicles. Am J Physiol. 238, F461-469.
Kopple, J. D., Bernard, D., Messana, J., Swartz, R., Bergstrom, J., Lindholm, B., Lim, V., Brunori, G., Leiserowitz, M., Bier, D. M. and et al., 1995. Treatment of malnourished CAPD patients with an amino acid based dialysate. Kidney Int. 47, 1148-1157.
Koyama, K., Okuyama, S., Fukuyama, T., Okamoto, Y., Kawasaki, J. and Miyao, H., 2003. [Blood lactate levels during fast-track cardiac anesthesia]. Masui. 52, 1191-1194.
Lagadic-Gossmann, D., Buckler, K. J. and Vaughan-Jones, R. D., 1992. Role of bicarbonate in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte. J Physiol. 458, 361-384.
Leem, C. H., Lagadic-Gossmann, D. and Vaughan-Jones, R. D., 1999. Characterization of intracellular pH regulation in the guinea-pig ventricular myocyte. J Physiol. 517 (Pt 1), 159-180.
Loh, S. H., Chen, W. H., Chiang, C. H., Tsai, C. S., Lee, G. C., Jin, J. S., Cheng, T. H. and Chen, J. J., 2002a. Intracellular pH regulatory mechanism in human atrial myocardium: functional evidence for Na(+)/H(+) exchanger and Na(+)/HCO(3)(-) symporter. J Biomed Sci. 9, 198-205.
Loh, S. H., Jin, J. S., Tsai, C. S., Chao, C. M., Chiung, C. S., Chen, W. H., Lin, C. I., Chuang, C. C. and Wei, J., 2002b. Functional evidence for intracellular acid extruders in human ventricular myocardium. Jpn J Physiol. 52, 277-284.
Loh, S. H., Sun, B. and Vaughan-Jones, R. D., 1996. Effect of Hoe 694, a novel Na(+)-H+ exchange inhibitor, on intracellular pH regulation in the guinea-pig ventricular myocyte. Br J Pharmacol. 118, 1905-1912.
Lysaght, M. J., Vonesh, E. F., Gotch, F., Ibels, L., Keen, M., Lindholm, B., Nolph, K. D., Pollock, C. A., Prowant, B. and Farrell, P. C., 1991. The influence of dialysis treatment modality on the decline of remaining renal function. ASAIO Trans. 37, 598-604.
Mactier, R. A., Sprosen, T. S., Gokal, R., Williams, P. F., Lindbergh, M., Naik, R. B., Wrege, U., Grontoft, K. C., Larsson, R., Berglund, J., Tranaeus, A. P. and Faict, D., 1998. Bicarbonate and bicarbonate/lactate peritoneal dialysis solutions for the treatment of infusion pain. Kidney Int. 53, 1061-1067.
Maiorca, R., Sandrini, S., Cancarini, G. C., Gaggia, P., Chiappini, R., Setti, G., Pola, A., Maffeis, R. and Cardillo, M., 1997. Integration of peritoneal dialysis and transplantation programs. Perit Dial Int. 17 Suppl 2, S170-174.
Malayev, A. and Nelson, D. J., 1995. Extracellular pH modulates the Ca2+ current activated by depletion of intracellular Ca2+ stores in human macrophages. J Membr Biol. 146, 101-111.
Mason, M. J. and Thomas, R. C., 1988. A microelectrode study of the mechanisms of L-lactate entry into and release from frog sartorius muscle. J Physiol. 400, 459-479.
Meiltz, A., Kucera, P., de Ribaupierre, Y. and Raddatz, E., 1998. Inhibition of bicarbonate transport protects embryonic heart against reoxygenation-induced dysfunction. J Mol Cell Cardiol. 30, 327-335.
Mistry, C. D., Gokal, R. and Peers, E., 1994. A randomized multicenter clinical trial comparing isosmolar icodextrin with hyperosmolar glucose solutions in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Peritoneal Dialysis. Kidney Int. 46, 496-503.
Mistry, C. D., Mallick, N. P. and Gokal, R., 1987. Ultrafiltration with an isosmotic solution during long peritoneal dialysis exchanges. Lancet. 2, 178-182.
Moody, S. E., Perez, D., Pan, T. C., Sarkisian, C. J., Portocarrero, C. P., Sterner, C. J., Notorfrancesco, K. L., Cardiff, R. D. and Chodosh, L. A., 2005. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 8, 197-209.
Moolenaar, W. H., Tsien, R. Y., van der Saag, P. T. and de Laat, S. W., 1983. Na+/H+ exchange and cytoplasmic pH in the action of growth factors in human fibroblasts. Nature. 304, 645-648.
Murer, H., Hopfer, U. and Kinne, R., 1976. Sodium/proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. Biochem J. 154, 597-604.
Mutsaers, S. E., 2002. Mesothelial cells: their structure, function and role in serosal repair. Respirology. 7, 171-191.
Nakamura, N., Tanaka, S., Teko, Y., Mitsui, K. and Kanazawa, H., 2005. Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J Biol Chem. 280, 1561-1572.
Numata, M. and Orlowski, J., 2001. Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem. 276, 17387-17394.
Orlowski, J. and Grinstein, S., 2004. Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch. 447, 549-565.
Pecoits-Filho, R., Araujo, M. R., Lindholm, B., Stenvinkel, P., Abensur, H., Romao, J. E., Jr., Marcondes, M., De Oliveira, A. H. and Noronha, I. L., 2002. Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate. Nephrol Dial Transplant. 17, 1480-1486.
Poole, R. C., Halestrap, A. P., Price, S. J. and Levi, A. J., 1989. The kinetics of transport of lactate and pyruvate into isolated cardiac myocytes from guinea pig. Kinetic evidence for the presence of a carrier distinct from that in erythrocytes and hepatocytes. Biochem J. 264, 409-418.
Portman, M. A., Panos, A. L., Xiao, Y., Anderson, D. L. and Ning, X., 2001. HOE-642 (cariporide) alters pH(i) and diastolic function after ischemia during reperfusion in pig hearts in situ. Am J Physiol Heart Circ Physiol. 280, H830-834.
Putnam, R. W., 1990. pH regulatory transport systems in a smooth muscle-like cell line. Am J Physiol. 258, C470-479.
Rich, I. N., Worthington-White, D., Garden, O. A. and Musk, P., 2000. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood. 95, 1427-1434.
Roos, A. and Boron, W. F., 1981. Intracellular pH. Physiol Rev. 61, 296-434.
Simon, S., Roy, D. and Schindler, M., 1994. Intracellular pH and the control of multidrug resistance. Proc Natl Acad Sci U S A. 91, 1128-1132.
Skelton, M. S., Kremer, D. E., Smith, E. W. and Gladden, L. B., 1998. Lactate influx into red blood cells from trained and untrained human subjects. Med Sci Sports Exerc. 30, 536-542.
Soleimani, M. and Burnham, C. E., 2001. Na+:HCO(3-) cotransporters (NBC): cloning and characterization. J Membr Biol. 183, 71-84.
Sun, B., Leem, C. H. and Vaughan-Jones, R. D., 1996. Novel chloride-dependent acid loader in the guinea-pig ventricular myocyte: part of a dual acid-loading mechanism. J Physiol. 495 (Pt 1), 65-82.
Thomas, J. A., Buchsbaum, R. N., Zimniak, A. and Racker, E., 1979. Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ. Biochemistry. 18, 2210-2218.
Topley, N., Kaur, D., Petersen, M. M., Jorres, A., Williams, J. D., Faict, D. and Holmes, C. J., 1996. In vitro effects of bicarbonate and bicarbonate-lactate buffered peritoneal dialysis solutions on mesothelial and neutrophil function. J Am Soc Nephrol. 7, 218-224.
Trivedi, B. and Danforth, W. H., 1966. Effect of pH on the kinetics of frog muscle phosphofructokinase. J Biol Chem. 241, 4110-4112.
Verger, C., Brunschvicg, O., Le Charpentier, Y., Lavergne, A. and Vantelon, J., 1981. Structural and ultrastructural peritoneal membrane changes and permeability alterations during continuous ambulatory peritoneal dialysis. Proc Eur Dial Transplant Assoc. 18, 199-205.
Wakabayashi, S., Fafournoux, P., Sardet, C. and Pouyssegur, J., 1992. The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls "H(+)-sensing". Proc Natl Acad Sci U S A. 89, 2424-2428.
Wang, X., Levi, A. J. and Halestrap, A. P., 1994. Kinetics of the sarcolemmal lactate carrier in single heart cells using BCECF to measure pHi. Am J Physiol. 267, H1759-1769.
Webb, S. D., Sherratt, J. A. and Fish, R. G., 1999. Mathematical modelling of tumour acidity: regulation of intracellular pH. J Theor Biol. 196, 237-250.
Whitaker, D., Papadimitriou, J. M. and Walters, M. N., 1982. The mesothelium and its reactions: a review. Crit Rev Toxicol. 10, 81-144.
Witowski, J., Wisniewska, J., Korybalska, K., Bender, T. O., Breborowicz, A., Gahl, G. M., Frei, U., Passlick-Deetjen, J. and Jorres, A., 2001. Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal mesothelial cells. J Am Soc Nephrol. 12, 2434-2441.
Wolfson, M., Ogrinc, F. and Mujais, S., 2002. Review of clinical trial experience with icodextrin. Kidney Int Suppl, S46-52.
Woodrow, G., Stables, G., Oldroyd, B., Gibson, J., Turney, J. H. and Brownjohn, A. M., 1999. Comparison of icodextrin and glucose solutions for the daytime dwell in automated peritoneal dialysis. Nephrol Dial Transplant. 14, 1530-1535.
Wu, M. L. and Vaughan-Jones, R. D., 1994. Effect of metabolic inhibitors and second messengers upon Na(+)-H+ exchange in the sheep cardiac Purkinje fibre. J Physiol. 478 (Pt 2), 301-313.
Yanez-Mo, M., Lara-Pezzi, E., Selgas, R., Ramirez-Huesca, M., Dominguez-Jimenez, C., Jimenez-Heffernan, J. A., Aguilera, A., Sanchez-Tomero, J. A., Bajo, M. A., Alvarez, V., Castro, M. A., del Peso, G., Cirujeda, A., Gamallo, C., Sanchez-Madrid, F. and Lopez-Cabrera, M., 2003. Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med. 348, 403-413.
Yang, A. H., Chen, J. Y. and Lin, J. K., 2003. Myofibroblastic conversion of mesothelial cells. Kidney Int. 63, 1530-1539.
Yoshio, Y., Miyazaki, M., Abe, K., Nishino, T., Furusu, A., Mizuta, Y., Harada, T., Ozono, Y., Koji, T. and Kohno, S., 2004. TNP-470, an angiogenesis inhibitor, suppresses the progression of peritoneal fibrosis in mouse experimental model. Kidney Int. 66, 1677-1685.
Young, G. A., Kopple, J. D., Lindholm, B., Vonesh, E. F., De Vecchi, A., Scalamogna, A., Castelnova, C., Oreopoulos, D. G., Anderson, G. H., Bergstrom, J. and et al., 1991. Nutritional assessment of continuous ambulatory peritoneal dialysis patients: an international study. Am J Kidney Dis. 17, 462-471.
Zweers, M. M., de Waart, D. R., Smit, W., Struijk, D. G. and Krediet, R. T., 1999. Growth factors VEGF and TGF-beta1 in peritoneal dialysis. J Lab Clin Med. 134, 124-132.