尿素通道蛋白的组织分布和生理功能

摘要/Abstract

摘要： 尿素通道蛋白（urea transporter，UT）是一类特异性通透尿素的跨膜蛋白，其包括两个亚家族。UT-A亚家族有6个成员（UT-A1~UT-A6），主要分布在肾脏。UT-B亚家族只有1个成员UT-B。UT-B分布广泛，在红细胞、肾脏、大脑、膀胱、睾丸、血管内皮等多组织器官表达。尿素通道蛋白在肾脏尿液浓缩过程中发挥重要作用，也参与其所表达组织器官的生理功能。本文主要综述尿素通道蛋白的组织分布及其生理学功能。

关键词: 尿素, 尿素通道蛋白, 肾脏, 尿浓缩机制, 生理学功能

Abstract: Urea transporters（ UT） are a class of transmembrane proteins that are selectively permeable to urea. There are two UT subfamilies，six members（ UT-A1-A6） in UT-A subfamily that are mainly expressed in kidney. There is only one member（ UT-B） in UT-B subfamily that is widely distributed in multiple tissues，including the red blood cell，kidney，brain，bladder，testis，etc. Urea transporters play an important role in the urine concentration mechanism，and are also involved in many other physiological functions. In this review article，we summarize the expression localization and physiological functions of urea transporters.

Key words: urea, urea transporter, kidney, urine concentration, physiological function

姜涛，杨宝学. 尿素通道蛋白的组织分布和生理功能[J]. 神经药理学报, 2015, 5(5): 40-48.

JIANG Tao，YANG Bao-xue. Tissue Localization and Physiological Functions of Urea Transporters[J]. Acta Neuropharmacologica, 2015, 5(5): 40-48.

参考文献

[1] Yang Bao-xue, Lise Bankir, Annemarie Gillespie, et al. Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B [J]. J Biol Chem, 2002, 277(12): 10633-10637.

[2] Sands J M, Knepper M A. Urea permeability of mammalian inner medullary collecting duct system and papillary surface epithelium [J]. J Clin Invest, 1987, 79(1): 138-147.

[3] You Guo-feng, Craig P Smith, Yoshikatsu Kanai, et al. Cloning and characterization of the vasopressin-regulated urea transporter [J]. Nature, 1993, 365(6449): 844-847.

[4] Serena M Bagnasco, Peng Tao, Michael G Janech, et al. Cloning and characterization of the human urea transporter UT-A1 and mapping of the human Slc14a2 gene [J]. Am J Physiol Renal Physiol, 2001, 281(3): F400-F406.

[5] Mitsi A Blount, Jae H Sim, Zhou Rong, et al. Expression of transporters involved in urine concentration recovers differently after cessation of lithium treatment [J].Am J Physiol Renal Physiol, 2010, 298(3): F601-F608.

[6] John J Doran, Janet D Klein, Young Hee Kim, et al. Tissue distribution of UT-A and UT-B mRNA and protein in rat [J]. Am J Physiol Regul Integr Comp Physiol, 2006, 290(5): R1446-R1459.

[7] Janet D Klein, Mitsi A Blount, Otto Frohlich, et al. Phosphorylation of UT-A1 on serine 486 correlates with membrane accumulation and urea transport activity in both rat IMCDs and cultured cells [J]. Am J Physiol Renal Physiol, 2010, 298(4): F935-F940.

[8] Naruse M, Klein J D, Ashkar Z M, et al. Glucocorticoids downregulate the vasopressin-regulated urea transporter in rat terminal inner medullary collecting ducts [J]. J Am Soc Nephrol, 1997, 8(4): 517-523.

[9] Soren Nielsen, James Terris, Craig P Smith, et al. Cellular and subcellular localization of the vasopressin- regulated urea transporter in rat kidney [J]. Proc Natl Acad Sci USA, 1996, 93(11): 5495-5500.

[10] Terris J, Ecelbarger C A, Sands J M, et al. Long-term regulation of renal urea transporter protein expression in rat [J]. J Am Soc Nephrol, 1998, 9(5): 729-736.

[11] Li Xue-chen, Yang Bao-xue, Chen Min-guang, et al. Activation of protein kinase C-alpha and Src kinase increases urea transporter A1 alpha-2, 6 sialylation [J].J Am Soc Nephrol, 2015, 26(4): 926-934.

[12] Young-Hee Kim, Dong-Un Kim, Ki-Hwan Han, et al. Expression of urea transporters in the developing rat kidney [J]. Am J Physiol Renal Physiol, 2002, 282(3): F530-F540.

[13] Bryce Maciver, Craig P Smith, Warren G Hill, et al. Functional characterization of mouse urea transporters UT-A2 and UT-A3 expressed in purified Xenopus laevis oocyte plasma membranes[J]. Am J Physiol Renal Physiol, 2008, 294(4): F956-F964.

[14] Thomas L Pallone, Zhang Zhong, Kristie Rhinehart. Physiology of the renal medullary microcirculation [J]. Am J Physiol Renal Physiol, 2003, 284(2): F253-F266.

[15] Thomas L Pannabecker, Cory S Henderson, William H Dantzler. Quantitative analysis of functional reconstructions reveals lateral and axial zonation in the renal inner medulla [J]. Am J Physiol Renal Physiol, 2008, 294(6): F1306-F1314.

[16] Justin Yuan, Thomas L Pannabecker. Architecture of inner medullary descending and ascending vasa recta: pathways for countercurrent exchange [J]. Am J Physiol Renal Physiol, 2010, 299(1): F265-F272.

[17] Martial S, Olives B, Abrami L, et al. Functional differentiation of the human red blood cell and kidney urea transporters [J]. Am J Physiol, 1996, 271(6 Pt 2): F1264-F1268.

[18] Mitsi A Blount, Janet D Klein, Christopher F Martin, et al. Forskolin stimulates phosphorylation and membrane accumulation of UT-A3 [J]. Am J Physiol Renal Physiol, 2007, 293(4): F1308-F1313.

[19] James M Terris, Mark A Knepper, James B Wade. UT-A3: localization and characterization of an additional urea transporter isoform in the IMCD [J]. Am J Physiol Renal Physiol, 2001, 280(2): F325-F332.

[20] Alexander Karakashian, Richard T Timmer, Janet D Klein, et al. Cloning and characterization of two new isoforms of the rat kidney urea transporter: UT-A3 and UT-A4 [J]. J Am Soc Nephrol, 1999, 10(2): 230-237.

[21] Fenton R A, Howorth A, Cooper G J, et al. Molecular characterization of a novel UT-A urea transporter isoform (UT-A5) in testis [J]. Am J Physiol Cell Physiol, 2000, 279(5): C1425-C1431.

[22] Craig P Smith, Elizabeth A Potter, Robert A Fenton, et al. Characterization of a human colonic cDNA encoding a structurally novel urea transporter, hUT-A6 [J]. Am J Physiol Cell Physiol, 2004, 287(4): C1087-C1093.

[23] Urs V Berger, Hiroyasu Tsukaguchi, Hediger M A. Distribution of mRNA for the facilitated urea transporter UT3 in the rat nervous system [J]. Anat Embryol (Berl), 1998, 197(5): 405-414.

[24] Hall G D, Smith B, Weeks R J, et al. Novel urothelium specific gene expression identified by differential display reverse transcriptase-polymerase chain reaction [J]. J Urol, 2006, 175(1): 337-342.

[25] Hideki Inoue, Shelley D Jackson, Tatyana Vikulina, et al. Identification and characterization of a Kidd antigen/UT-B urea transporter expressed in human colon [J]. Am J Physiol Cell Physiol, 2004, 287(1): C30-C35.

[26] Yong-Sig Kwun, Sang W Yeo, Yang-Heui Ahn, et al. Immunohistochemical localization of urea transporters A and B in the rat cochlea [J]. Hear Res, 2003, 183(1-2): 84-96.

[27] Lucien N, Bruneval P, Lasbennes F, et al. UT-B1 urea transporter is expressed along the urinary and gastrointestinal tracts of the mouse [J]. Am J Physiol Regul Integr Comp Physiol, 2005, 288(4): R1046-R1056.

[28] Nicole Lucien, Frederic Sidoux-Walter, Nathalie Roudier, et al. Antigenic and functional properties of the human red blood cell urea transporter hUT-B1 [J]. J Biol Chem, 2002, 277(37): 34101-34108.

[29] Bemadette Olives, Sonia Martial, Marie-Genevieve Mattei, et al. Molecular characterization of a new urea transporter in the human kidney [J]. Febs Lett, 1996, 386(2-3): 156-160.

[30] Bernadette Olives, Philippe Neau, Pascal Bailly, et al. Cloning and functional expression of a urea transporter from human bone marrow cells [J]. J Biol Chem, 1994, 269(50): 31649-31652.

[31] William P Prichett, Amanda J Patton, John A Field, et al. Identification and cloning of a human urea transporter HUT11, which is downregulated during adipogenesis of explant cultures of human bone [J]. J Cell Biochem, 2000, 76(4): 639-650.

[32] Richard T Timmer, Janet D Klein, Serena M Bagnasco, et al. Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues [J]. Am J Physiol Cell Physiol, 2001, 281(4): C1318-C1325.

[33] You G, Smith C P, Kanai Y, et al. Cloning and characterization of the vasopressin-regulated urea transporter [J]. Nature, 1993, 365(6449): 844-847.

[34] Thomas L Pannabecker, William H Dantzler, Harold E Layton, et al. Role of three-dimensional architecture in the urine concentrating mechanism of the rat renal inner medulla [J]. Am J Physiol Renal Physiol, 2008, 295(5): F1271-F1285.

[35] David A Spector, Yang Qing, James B Wade. High urea and creatinine concentrations and urea transporter B in mammalian urinary tract tissues [J]. Am J Physiol Renal Physiol, 2007, 292(1): F467-F474.

[36] Zhao Dan, Sonawane N D, Marc H Levin, et al. Comparative transport efficiencies of urea analogues through urea transporter UT-B [J]. Biochim Biophys Acta, 2007, 1768(7): 1815-1821.

[37] Zhong Dan-dan, Yang Bao-xue. Transport characteristics of urea transporter-B [J]. Subcell Biochem, 2014, 73: 127-135.

[38] Yang Bao-xue, Verkman A S. Urea transporter UT3 functions as an efficient water channel. Direct evidence for a common water/urea pathway [J]. J Biol Chem, 1998, 273(16): 9369-9372.

[39] Li Xin, Ran Jian-hua, Zhou Hong, et al. Mice lacking urea transporter UT-B display depression-like behavior [J]. J Mol Neurosci, 2012, 46(2): 362-372.

[40] Cecile Couriaud, Pierre Ripoche, Germain Rousselet. Cloning and functional characterization of a rat urea transporter: expression in the brain [J]. Biochim Biophys Acta, 1996, 1309(3): 197-199.

[41] Yang Bao-xue, Li Xin, Guo Li-rong, et al. Extrarenal phenotypes of the UT-B knockout mouse [J]. Subcell Biochem, 2014, 73: 153-164.

[42] R Douglas Fields. White matter in learning, cognition and psychiatric disorders [J]. Trends Neurosci, 2008, 31(7): 361-370.

[43] Luo Lan, Tan Ren-xiang. Fluoxetine inhibits dendrite atrophy of hippocampal neurons by decreasing nitric oxide synthase expression in rat depression model [J]. Acta Pharmacol Sin, 2001, 22(10): 865-870.

[44] Xiao Shen, Laszlo Wagner, James Mahaney, et al. Uremic levels of urea inhibit L-arginine transport in cultured endothelial cells [J]. Am J Physiol Renal Physiol, 2001, 280(6): F989-F995.

[45] Laszlo Wagner, Janet D Klein, Jeff M Sands, et al. Urea transporters are distributed in endothelial cells and mediate inhibition of L-arginine transport [J]. Am J Physiol Renal Physiol, 2002, 283(3): F578-F582.

[46] Alan J Thomas, John T O'Brien, Sue Davis, et al. Ischemic basis for deep white matter hyperintensities in major depression: a neuropathological study [J]. Arch Gen Psychiatry, 2002, 59(9): 785-792.

[47] Jeff M Sands. Molecular approaches to urea transporters [J]. J Am Soc Nephrol, 2002, 13(11): 2795-2806.

[48] Macey R I, Yousef L W. Osmotic stability of red cells in renal circulation requires rapid urea transport [J]. Am J Physiol, 1988, 254(5 Pt 1): C669-C674.

[49] Lieberthal W, Stephens G W, Wolf E F, et al. Effect of erythrocytes on the function and morphology of the isolated perfused rat kidney [J]. Ren Physiol, 1987, 10(1): 14-24.

[50] Liu Li-feng, Lei Tian-luo, Lise Bankir, et al. Erythrocyte permeability to urea and water: comparative study in rodents, ruminants, carnivores, humans, and birds [J]. J Comp Physiol B, 2011, 181(1): 65-72.

[51] Li Xue-chen, Chen Guang-ping, Yang Bao-xue. Urea transporter physiology studied in knockout mice [J]. Front Physiol, 2012, 3: 217.

[52] Rafael Duchesne, Janet D Klein, Jeffrey B Velotta, et al. UT-A urea transporter protein in heart: increased abundance during uremia, hypertension, and heart failure [J]. Circ Res, 2001, 89(2): 139-145.

[53] Meng Yan, Zhao Chun-yan, Zhang Xue-xin, et al. Surface electrocardiogram and action potential in mice lacking urea transporter UT-B [J]. Sci China C Life Sci, 2009, 52(5): 474-478.

[54] James Scheuer, S William Stezoski. The effects of uremic compounds on cardiac function and metabolism [J]. J Mol Cell Cardiol, 1973, 5(3): 287-300.

[55] Ray E Hershberger, Jose Renato Pinto, Sharie B Parks, et al. Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy [J]. Circ Cardiovasc Genet, 2009, 2(4): 306-313.

[56] Yu H, Meng Y, Wang LS, et al. Differential protein expression in heart in UT-B null mice with cardiac conduction defects [J]. Proteomics, 2009, 9(3): 504-511.

[57] Mark Schneider, Michael Boffa, Ronald Stewart, et al. Two naturally occurring variants of TAFI (Thr-325 and Ile-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme [J]. J Biol Chem, 2002, 277(2): 1021-1030.

[58] Sun Yi, Lau Chi-wai, Jia Ying-li, et al. Functional inhibition of urea transporter UT-B enhances endothelial-dependent vasodilation and lowers blood pressure via L-arginine-endothelial nitric oxide synthase-nitric oxide pathway [J]. Sci Rep, 2015, 5:16910. doi: 10.1038/srep 18697.

[59] Yang Bao-xue, Lise Bankir, Annemarie Gillespie, et al. Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B [J]. J Biol Chem, 2002, 277(12): 10633-10637.

[60] Fenton R A, Yang B. Urea transporter knockout mice and their renal phenotypes [J]. Subcell Biochem, 2014, 73: 137-152.

[61] Lise Bankir, Chen Kai, Yang Bao-xue. Lack of UT-B in vasa recta and red blood cells prevents urea-induced improvement of urinary concentrating ability [J]. Am J Physiol Renal Physiol, 2004, 286(1): F144-F151.

[62] Yang Bao-xue, Lise Bankir. Urea and urine concentrating ability: new insights from studies in mice [J]. Am J Physiol Renal Physiol, 2005, 288(5): F881-F896.

[63] Alan S Verkman, Cristina Esteva-Font, Onur Cil, et al. Small-molecule inhibitors of urea transporters [J]. Subcell Biochem, 2014, 73: 165-177.

[64] Li Min, Weng Ieong Tou, Zhou Hong, et al. Developing hypothetical inhibition mechanism of novel urea transporter B inhibitor [J]. Sci Rep, 2014, 4: 5775.

[65] Li F, Lei T, Zhu J, et al. A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic [J]. Kidney Int, 2013, 83(6): 1076-1086.

[66] Ren H, Wang Y, Xing Y, et al. Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters [J]. Am J Physiol Renal Physiol, 2014, 307(12): F1363-F1372.

[67] Lise Bankir, Yang Bao-xue. New insights into urea and glucose handling by the kidney, and the urine concentrating mechanism [J]. Kidney Int, 2012, 81(12): 1179-1198.

[68] Robert A Fenton, Chung-Lin Chou, Gavin S Stewart, et al. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct [J]. Proc Natl Acad Sci USA, 2004, 101(19): 7469-7474.

[69] Jeff M Sands. Mammalian urea transporters [J]. Annu Rev Physiol, 2003, 65: 543-566.

[70] Robert A Fenton, Anneliese Flynn, Adetola Shodeinde, et al. Renal phenotype of UT-A urea transporter knockout mice [J]. J Am Soc Nephrol, 2005, 16(6): 1583-1592.

[71] Fenton R A. Urea transporters and renal function: lessons from knockout mice [J]. Curr Opin Nephrol Hypertens, 2008, 17(5): 513-518.

[72] Shinichi Uchida, Eisei Sohara, Tatemitsu Rai, et al. Impaired urea accumulation in the inner medulla of mice lacking the urea transporter UT-A2 [J]. Mol Cell Biol, 2005, 25(16): 7357-7363.

[73] Lei Tian-luo, Zhou Lei, Anita T Layton, et al. Role of thin descending limb urea transport in renal urea handling and the urine concentrating mechanism [J]. Am J Physiol Renal Physiol, 2011, 301(6): F1251-F1259.

[74] Janet D Klein, Jeff M Sands, Qian Li-man, et al. Upregulation of urea transporter UT-A2 and water channels AQP2 and AQP3 in mice lacking urea transporter UT-B [J]. J Am Soc Nephrol, 2004, 15(5): 1161-1167.

[75] Hu Ming-chang, Lise Bankir, Stephanie Michelet, et al. Massive reduction of urea transporters in remnant kidney and brain of uremic rats [J]. Kidney Int, 2000, 58(3): 1202-1210.

[76] Tsukaguchi H, Shayakul C, Berger UV, et al. Cloning and characterization of the urea transporter UT3: localization in rat kidney and testis [J]. J Clin Invest, 1997, 99(7): 1506-1515.

[77] Guo Li-rong, Zhao Dan, Song Yuan-lin, et al. Reduced urea flux across the blood-testis barrier and early maturation in the male reproductive system in UT-B-null mice [J]. Am J Physiol Cell Physiol, 2007, 293(1): C305-C312.

[78] Hanumanthappa Krishnamurthy, Poda Suresh Babu, Carlos R Morales, et al. Delay in sexual maturity of the follicle-stimulating hormone receptor knockout male mouse [J]. Biol Reprod, 2001, 65(2): 522-531.

[79] Dong Zi-xun, Ran Jian-hua, Zhou Hong, et al. Urea transporter UT-B deletion induces DNA damage and apoptosis in mouse bladder urothelium [J]. PLoS One, 2013, 8(10): e76952.

[80] Kraus L M, Kraus A J. Carbamoylation of amino acids and proteins in uremia [J]. Kidney Int Suppl, 2001, 78: S102-S107.

[81] Zhang Zheng, Natalia I Dmitrieva, Jong-Hwan Park, et al. High urea and NaCl carbonylate proteins in renal cells in culture and in vivo, and high urea causes 8-oxoguanine lesions in their DNA [J]. Proc Natl Acad Sci USA, 2004, 101(25): 9491-9496.

[82] Ahsan U Khan, Paolo Di Mascio, Marisa H Medeiros, et al. Spermine and spermidine protection of plasmid DNA against single-strand breaks induced by singlet oxygen [J]. Proc Natl Acad Sci USA, 1992, 89(23): 11428-1130.

[83] Ahsan U Khan, Mei Ying-Hua, Therese Wilson. A proposed function for spermine and spermidine: protection of replicating DNA against damage by singlet oxygen [J]. Proc Natl Acad Sci U S A, 1992, 89(23): 11426-11427.

[84] Zou Qin, Susan M Habermann-Rottinghaus, Kenneth P Murphy. Urea effects on protein stability: hydrogen bonding and the hydrophobic effect [J]. Proteins, 1998, 31(2): 107-115.

[85] Thorunn Rafnar, Sita H Vermeulen, Patrick Sulem, et al. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene [J]. Hum Mol Genet, 2011, 20(21): 4268-4281.

[86] Janet D Klein, Richard T Timmer, Patricia Rouillard, et al. UT-A urea transporter protein expressed in liver: upregulation by uremia [J]. J Am Soc Nephrol, 1999, 10(10): 2076-2083.

[87] Sands J M. Regulation of urea transporter proteins in kidney and liver [J]. Mt Sinai J Med, 2000, 67(2): 112-119.

[88] Hideki Inoue, Shelley D Kozlowski, Janet D Klein, et al. Regulated expression of renal and intestinal UT-B urea transporter in response to varying urea load [J]. Am J Physiol Renal Physiol, 2005, 289(2): F451-F458.