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Mini-Review Article

Urea Transporters Identified as Novel Diuretic Drug Targets

Author(s): Min Li, Shun Zhang and Baoxue Yang*

Volume 21, Issue 3, 2020

Page: [279 - 287] Pages: 9

DOI: 10.2174/1389450120666191129101915

Price: $65

Abstract

Background: Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups, UT-A and UT-B. UT-As are primarily located in renal tubule epithelia and UT-Bs are highly expressed in renal descending vasa recta and extrarenal multiple tissues. Various urea transporter knockout mice exhibit low urine concentrating ability, which suggests that UTs are novel diuretic targets. With highthroughput screening of small molecule drug-like compound libraries, various potent UT inhibitors with IC50 at nanomolar level were identified. Furthermore, selective UT inhibitors exhibit diuretic activity without disturbing electrolyte and metabolism balance, which confirms the potential of UTs as diuretic targets and UT inhibitors as novel diuretics that do not cause electrolyte imbalance.

Objective: This review article summarizes the identification and validation of urea transporter as a potential diuretic target and the discovery of small molecule UT inhibitors as a novel type of diuretics.

Conclusion: UTs are a potential diuretic target. UT inhibitors play significant diuresis and can be developed to diuretics without disturbing electrolyte balance.

Keywords: Urea transporter, diuretic target, inhibitor, drug discovery, molecular dynamics, electrolyte balance.

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[1]
Calderone V, Martelli A, Piragine E, Citi V, Testai L, Breschi MC. the renal outer medullary potassium channel (romk): an intriguing pharmacological target for an innovative class of diuretic drugs. Curr Med Chem 2018; 25(23): 2627-36.
[http://dx.doi.org/10.2174/0929867324666171012120937] [PMID: 29022503]
[2]
Palazzuoli A, Ruocco G, Pellegrini M, Beltrami M, Del Castillo G, Nuti R. Loop diuretics strategies in acute heart failure: from clinical trials to practical application. Curr Drug Targets 2015; 16(11): 1246-53.
[http://dx.doi.org/10.2174/1389450116666150420125531] [PMID: 25892312]
[3]
Zhang L, Hussain Z, Ren Z. Recent advances in rational diagnosis and treatment of normal pressure hydrocephalus: a critical appraisal on novel diagnostic, therapy monitoring and treatment modalities. Curr Drug Targets 2019; 20(10): 1041-57.
[http://dx.doi.org/10.2174/1389450120666190214121342] [PMID: 30767741]
[4]
Huxel C, Raja A. Ollivierre-lawrence md loop diuretics. Treasure Island, FL: StatPearls 2019.
[5]
Akbari P, Khorasani-Zadeh A. Thiazide Diuretics. Treasure Island, FL: StatPearls 2019.
[6]
Blowey DL. Diuretics in the treatment of hypertension. Pediatr Nephrol 2016; 31(12): 2223-33.
[http://dx.doi.org/10.1007/s00467-016-3334-4] [PMID: 26983630]
[7]
Shrimanker I, Bhattarai S. Electrolytes. Treasure Island, FL: StatPearls 2019.
[8]
Mann SJ. The silent epidemic of thiazide-induced hyponatremia. J Clin Hypertens (Greenwich) 2008; 10(6): 477-84.
[http://dx.doi.org/10.1111/j.1751-7176.2008.08126.x] [PMID: 18550938]
[9]
Yang SS, Lo YF, Wu CC, et al. SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol 2010; 21(11): 1868-77.
[http://dx.doi.org/10.1681/ASN.2009121295] [PMID: 20813865]
[10]
Xiao Y, Meng XX, Zhang H, Guo XW, Gu RM. The function and regulation of basolateral Kir4.1 and Kir4.1/Kir5.1 in renal tubules Sheng li xue bao : [Acta physiologica Sinica 2018; 70(6): 600.
[11]
Marcoux AA, Slimani S, Tremblay LE, Frenette-Cotton R, Garneau AP, Isenring P. Regulation of Na+-K+-Cl- cotransporter type 2 by the with no lysine kinase-dependent signaling pathway. Am J Physiol Cell Physiol 2019; 317(1): C20-30.
[http://dx.doi.org/10.1152/ajpcell.00041.2019] [PMID: 30917032]
[12]
Matsumura Y, Uchida S, Kondo Y, et al. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nat Genet 1999; 21(1): 95-8.
[http://dx.doi.org/10.1038/5036] [PMID: 9916798]
[13]
Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006; 69(12): 2124-30.
[http://dx.doi.org/10.1038/sj.ki.5000432] [PMID: 16672911]
[14]
Fukui H. Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites? World J Gastroenterol 2015; 21(41): 11584-96.
[http://dx.doi.org/10.3748/wjg.v21.i41.11584] [PMID: 26556988]
[15]
Thibonnier M, Coles P, Thibonnier A, Shoham M. The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu Rev Pharmacol Toxicol 2001; 41: 175-202.
[http://dx.doi.org/10.1146/annurev.pharmtox.41.1.175] [PMID: 11264455]
[16]
Ginès P, Wong F, Watson H, Milutinovic S, del Arbol LR, Olteanu D. HypoCAT Study Investigators. Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial. Hepatology 2008; 48(1): 204-13.
[http://dx.doi.org/10.1002/hep.22293] [PMID: 18508290]
[17]
Sands JM. Urea transporter inhibitors: en route to new diuretics. Chem Biol 2013; 20(10): 1201-2.
[http://dx.doi.org/10.1016/j.chembiol.2013.10.003] [PMID: 24210002]
[18]
Sands JM, Knepper MA. Urea permeability of mammalian inner medullary collecting duct system and papillary surface epithelium. J Clin Invest 1987; 79(1): 138-47.
[http://dx.doi.org/10.1172/JCI112774] [PMID: 3793921]
[19]
You G, Smith CP, Kanai Y, Lee WS, Stelzner M, Hediger MA. Cloning and characterization of the vasopressin-regulated urea transporter. Nature 1993; 365(6449): 844-7.
[http://dx.doi.org/10.1038/365844a0] [PMID: 8413669]
[20]
Yang B, Bankir L. Urea and urine concentrating ability: new insights from studies in mice. Am J Physiol Renal Physiol 2005; 288(5): F881-96.
[http://dx.doi.org/10.1152/ajprenal.00367.2004] [PMID: 15821253]
[21]
Fenton RA, Cottingham CA, Stewart GS, Howorth A, Hewitt JA, Smith CP. Structure and characterization of the mouse UT-A gene (Slc14a2). Am J Physiol Renal Physiol 2002; 282(4): F630-8.
[http://dx.doi.org/10.1152/ajprenal.00264.2001] [PMID: 11880324]
[22]
Kim YH, Kim DU, Han KH, et al. Expression of urea transporters in the developing rat kidney. Am J Physiol Renal Physiol 2002; 282(3): F530-40.
[http://dx.doi.org/10.1152/ajprenal.00246.2001] [PMID: 11832436]
[23]
Karakashian A, Timmer RT, Klein JD, Gunn RB, Sands JM, Bagnasco SM. Cloning and characterization of two new isoforms of the rat kidney urea transporter: UT-A3 and UT-A4. J Am Soc Nephrol 1999; 10(2): 230-7.
[PMID: 10215321]
[24]
Bagnasco SM, Peng T, Nakayama Y, Sands JM. Differential expression of individual UT-A urea transporter isoforms in rat kidney. J Am Soc Nephrol 2000; 11(11): 1980-6.
[PMID: 11053472]
[25]
Fenton RA, Stewart GS, Carpenter B, et al. Characterization of mouse urea transporters UT-A1 and UT-A2. Am J Physiol Renal Physiol 2002; 283(4): F817-25.
[http://dx.doi.org/10.1152/ajprenal.00263.2001] [PMID: 12217874]
[26]
Smith CP, Lee WS, Martial S, et al. Cloning and regulation of expression of the rat kidney urea transporter (rUT2). J Clin Invest 1995; 96(3): 1556-63.
[http://dx.doi.org/10.1172/JCI118194] [PMID: 7657826]
[27]
Olives B, Neau P, Bailly P, et al. Cloning and functional expression of a urea transporter from human bone marrow cells. J Biol Chem 1994; 269(50): 31649-52.
[PMID: 7989337]
[28]
Bagnasco SM. Gene structure of urea transporters. Am J Physiol Renal Physiol 2003; 284(1): F3-F10.
[http://dx.doi.org/10.1152/ajprenal.00260.2002] [PMID: 12473534]
[29]
Doran JJ, Klein JD, Kim YH, et al. Tissue distribution of UT-A and UT-B mRNA and protein in rat. Am J Physiol Regul Integr Comp Physiol 2006; 290(5): R1446-59.
[http://dx.doi.org/10.1152/ajpregu.00352.2004] [PMID: 16373440]
[30]
Sun Y, Lau CW, Jia Y, et al. Functional inhibition of urea transporter UT-B enhances endothelial-dependent vasodilatation and lowers blood pressure via L-arginine-endothelial nitric oxide synthase-nitric oxide pathway. Sci Rep 2016; 6: 18697.
[http://dx.doi.org/10.1038/srep18697] [PMID: 26739766]
[31]
Shayakul C, Clémençon B, Hediger MA. The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol Aspects Med 2013; 34(2-3): 313-22.
[http://dx.doi.org/10.1016/j.mam.2012.12.003] [PMID: 23506873]
[32]
Shayakul C, Hediger MA. The SLC14 gene family of urea transporters. Pflugers Arch 2004; 447(5): 603-9.
[http://dx.doi.org/10.1007/s00424-003-1124-x] [PMID: 12856182]
[33]
Minocha R, Studley K, Saier MH Jr. The urea transporter (UT) family: bioinformatic analyses leading to structural, functional, and evolutionary predictions. Receptors Channels 2003; 9(6): 345-52.
[http://dx.doi.org/10.3109/714041015] [PMID: 14698962]
[34]
Levin EJ, Zhou M. Structure of urea transporters. Subcell Biochem 2014; 73: 65-78.
[http://dx.doi.org/10.1007/978-94-017-9343-8_5] [PMID: 25298339]
[35]
Rousselet G, Ripoche P, Bailly P. Tandem sequence repeats in urea transporters: identification of an urea transporter signature sequence. Am J Physiol 1996; 270(3 Pt 2): F554-5.
[PMID: 8780260]
[36]
Levin EJ, Cao Y, Enkavi G, et al. Structure and permeation mechanism of a mammalian urea transporter. Proc Natl Acad Sci USA 2012; 109(28): 11194-9.
[http://dx.doi.org/10.1073/pnas.1207362109] [PMID: 22733730]
[37]
Klein JD, Blount MA, Sands JM. Urea transport in the kidney. Compr Physiol 2011; 1(2): 699-729.
[PMID: 23737200]
[38]
Barmore W, Stone WL. Physiology, Urea Cycle. Treasure Island, FL: StatPearls 2019.
[39]
Pannabecker TL. Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla. Am J Physiol Regul Integr Comp Physiol 2013; 304(7): R488-503.
[http://dx.doi.org/10.1152/ajpregu.00456.2012] [PMID: 23364530]
[40]
Sands JM, Layton HE. The physiology of urinary concentration: an update. Semin Nephrol 2009; 29(3): 178-95.
[http://dx.doi.org/10.1016/j.semnephrol.2009.03.008] [PMID: 19523568]
[41]
Fenton RA. Urea transporters and renal function: lessons from knockout mice. Curr Opin Nephrol Hypertens 2008; 17(5): 513-8.
[http://dx.doi.org/10.1097/MNH.0b013e3283050969] [PMID: 18695393]
[42]
Fenton RA. Essential role of vasopressin-regulated urea transport processes in the mammalian kidney. Pflugers Arch 2009; 458(1): 169-77.
[http://dx.doi.org/10.1007/s00424-008-0612-4] [PMID: 19011892]
[43]
Sands JM. Critical role of urea in the urine-concentrating mechanism. J Am Soc Nephrol 2007; 18(3): 670-1.
[http://dx.doi.org/10.1681/ASN.2006121314] [PMID: 17251382]
[44]
Yang B, Bankir L, Gillespie A, Epstein CJ, Verkman AS. Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B. J Biol Chem 2002; 277(12): 10633-7.
[http://dx.doi.org/10.1074/jbc.M200207200] [PMID: 11792714]
[45]
Fenton RA, Knepper MA. Urea and renal function in the 21st century: insights from knockout mice. J Am Soc Nephrol 2007; 18(3): 679-88.
[http://dx.doi.org/10.1681/ASN.2006101108] [PMID: 17251384]
[46]
Sands JM. Renal urea transporters. Curr Opin Nephrol Hypertens 2004; 13(5): 525-32.
[http://dx.doi.org/10.1097/00041552-200409000-00008] [PMID: 15300159]
[47]
Sands JM, Layton HE. Advances in understanding the urine-concentrating mechanism. Annu Rev Physiol 2014; 76: 387-409.
[http://dx.doi.org/10.1146/annurev-physiol-021113-170350] [PMID: 24245944]
[48]
Klein JD, Blount MA, Sands JM. Molecular mechanisms of urea transport in health and disease. Pflugers Arch 2012; 464(6): 561-72.
[http://dx.doi.org/10.1007/s00424-012-1157-0] [PMID: 23007461]
[49]
Sands JM, Gargus JJ, Fröhlich O, Gunn RB, Kokko JP. Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport. J Am Soc Nephrol 1992; 2(12): 1689-96.
[PMID: 1498276]
[50]
Li X, Ran J, Zhou H, Lei T, Zhou L, Han J, et al. Mice lacking urea transporter UT-B display depression-like behavior. MN 2012; 46(2): 362-72.
[http://dx.doi.org/10.1007/s12031-011-9594-3]
[51]
Meng Y, Zhao C, Zhang X, et al. Surface electrocardiogram and action potential in mice lacking urea transporter UT-B. Sci China C Life Sci 2009; 52(5): 474-8.
[http://dx.doi.org/10.1007/s11427-009-0047-y] [PMID: 19471871]
[52]
Guo L, Zhao D, Song Y, et al. Reduced urea flux across the blood-testis barrier and early maturation in the male reproductive system in UT-B-null mice. Am J Physiol Cell Physiol 2007; 293(1): C305-12.
[http://dx.doi.org/10.1152/ajpcell.00608.2006] [PMID: 17475664]
[53]
Fenton RA, Chou CL, Stewart GS, Smith CP, Knepper MA. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc Natl Acad Sci USA 2004; 101(19): 7469-74.
[http://dx.doi.org/10.1073/pnas.0401704101] [PMID: 15123796]
[54]
Fenton RA, Flynn A, Shodeinde A, Smith CP, Schnermann J, Knepper MA. Renal phenotype of UT-A urea transporter knockout mice. J Am Soc Nephrol 2005; 16(6): 1583-92.
[http://dx.doi.org/10.1681/ASN.2005010031] [PMID: 15829709]
[55]
Klein JD, Wang Y, Mistry A, et al. Transgenic restoration of urea transporter a1 confers maximal urinary concentration in the absence of urea transporter a3. J Am Soc Nephrol 2016; 27(5): 1448-55.
[http://dx.doi.org/10.1681/ASN.2014121267] [PMID: 26407594]
[56]
Uchida S, Sohara E, Rai T, Ikawa M, Okabe M, Sasaki S. Impaired urea accumulation in the inner medulla of mice lacking the urea transporter UT-A2. Mol Cell Biol 2005; 25(16): 7357-63.
[http://dx.doi.org/10.1128/MCB.25.16.7357-7363.2005] [PMID: 16055743]
[57]
Jiang T, Li Y, Layton AT, et al. Generation and phenotypic analysis of mice lacking all urea transporters. Kidney Int 2017; 91(2): 338-51.
[http://dx.doi.org/10.1016/j.kint.2016.09.017] [PMID: 27914708]
[58]
Esteva-Font C, Phuan PW, Anderson MO, Verkman AS. A small molecule screen identifies selective inhibitors of urea transporter UT-A. Chem Biol 2013; 20(10): 1235-44.
[http://dx.doi.org/10.1016/j.chembiol.2013.08.005] [PMID: 24055006]
[59]
Knepper MA, Miranda CA. Urea channel inhibitors: a new functional class of aquaretics. Kidney Int 2013; 83(6): 991-3.
[http://dx.doi.org/10.1038/ki.2013.94] [PMID: 23728001]
[60]
Tsuchiya Y, Vidaurre D, Toh S, et al. A small-molecule screen identifies new functions for the plant hormone strigolactone. Nat Chem Biol 2010; 6(10): 741-9.
[http://dx.doi.org/10.1038/nchembio.435] [PMID: 20818397]
[61]
Bankir L, Yang B. New insights into urea and glucose handling by the kidney, and the urine concentrating mechanism. Kidney Int 2012; 81(12): 1179-98.
[http://dx.doi.org/10.1038/ki.2012.67] [PMID: 22456603]
[62]
Zhang Z, Dmitrieva NI, Park JH, Levine RL, Burg MB. High urea and NaCl carbonylate proteins in renal cells in culture and in vivo, and high urea causes 8-oxoguanine lesions in their DNA. Proc Natl Acad Sci USA 2004; 101(25): 9491-6.
[http://dx.doi.org/10.1073/pnas.0402961101] [PMID: 15190183]
[63]
Durante W, Johnson FK, Johnson RA. Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol 2007; 34(9): 906-11.
[http://dx.doi.org/10.1111/j.1440-1681.2007.04638.x] [PMID: 17645639]
[64]
Dong Z, Ran J, Zhou H, et al. Urea transporter UT-B deletion induces DNA damage and apoptosis in mouse bladder urothelium. PLoS One 2013; 8(10)e76952
[http://dx.doi.org/10.1371/journal.pone.0076952] [PMID: 24204711]
[65]
Li X, Chen G, Yang B. Urea transporter physiology studied in knockout mice. Front Physiol 2012; 3: 217.
[http://dx.doi.org/10.3389/fphys.2012.00217] [PMID: 22745630]
[66]
Chou CL, Knepper MA. Inhibition of urea transport in inner medullary collecting duct by phloretin and urea analogues. Am J Physiol 1989; 257(3 Pt 2): F359-65.
[PMID: 2506765]
[67]
Levin MH, de la Fuente R, Verkman AS. Urearetics: a small molecule screen yields nanomolar potency inhibitors of urea transporter UT-B. FASEB J 2007; 21(2): 551-63.
[http://dx.doi.org/10.1096/fj.06-6979com] [PMID: 17202246]
[68]
Yao C, Anderson MO, Zhang J, Yang B, Phuan PW, Verkman AS. Triazolothienopyrimidine inhibitors of urea transporter UT-B reduce urine concentration. J Am Soc Nephrol 2012; 23(7): 1210-20.
[http://dx.doi.org/10.1681/ASN.2011070751] [PMID: 22491419]
[69]
Cil O, Esteva-Font C, Tas ST, et al. Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats. Kidney Int 2015; 88(2): 311-20.
[http://dx.doi.org/10.1038/ki.2015.138] [PMID: 25993324]
[70]
Liu Y, Esteva-Font C, Yao C, Phuan PW, Verkman AS, Anderson MO. 1,1-Difluoroethyl-substituted triazolothienopyrimidines as inhibitors of a human urea transport protein (UT-B): new analogs and binding model. Bioorg Med Chem Lett 2013; 23(11): 3338-41.
[http://dx.doi.org/10.1016/j.bmcl.2013.03.089] [PMID: 23597791]
[71]
Lee S, Esteva-Font C, Phuan PW, Anderson MO, Verkman AS. Discovery, synthesis and structure-activity analysis of symmetrical 2,7-disubstituted fluorenones as urea transporter inhibitors. MedChemComm 2015; 6: 1278-84.
[http://dx.doi.org/10.1039/C5MD00198F] [PMID: 26191399]
[72]
Esteva-Font C, Phuan PW, Lee S, Su T, Anderson MO, Verkman AS. Structure-activity analysis of thiourea analogs as inhibitors of UT-A and UT-B urea transporters. Biochim Biophys Acta 2015; 1848(5): 1075-80.
[http://dx.doi.org/10.1016/j.bbamem.2015.01.004] [PMID: 25613743]
[73]
Li F, Lei T, Zhu J, et al. A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic. Kidney Int 2013; 83(6): 1076-86.
[http://dx.doi.org/10.1038/ki.2013.62] [PMID: 23486518]
[74]
Salmaso V, Moro S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: an overview. Front Pharmacol 2018; 9: 923.
[http://dx.doi.org/10.3389/fphar.2018.00923] [PMID: 30186166]
[75]
de Azevedo WF Jr. Molecular dynamics simulations of protein targets identified in Mycobacterium tuberculosis. Curr Med Chem 2011; 18(9): 1353-66.
[http://dx.doi.org/10.2174/092986711795029519] [PMID: 21366529]
[76]
Xavier MM, Heck GS, Avila MB, et al. SAnDReS a Computational tool for statistical analysis of docking results and development of scoring functions. Comb Chem High Throughput Screen 2016; 19(10): 801-12.
[http://dx.doi.org/10.2174/1386207319666160927111347] [PMID: 27686428]
[77]
Li M, Tou WI, Zhou H, et al. Developing hypothetical inhibition mechanism of novel urea transporter B inhibitor. Sci Rep 2014; 4: 5775.
[http://dx.doi.org/10.1038/srep05775] [PMID: 25047372]
[78]
Ren H, Wang Y, Xing Y, et al. Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters. Am J Physiol Renal Physiol 2014; 307(12): F1363-72.
[http://dx.doi.org/10.1152/ajprenal.00421.2014] [PMID: 25298523]
[79]
Zhang ZY, Zhang H, Liu D, et al. Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats. Pharmaceutics 2018; 10(3)E124
[http://dx.doi.org/10.3390/pharmaceutics10030124] [PMID: 30096833]
[80]
Zhang ZY, Wang X, Liu D, Zhang H, Zhang Q, Lu YY, et al. Development and validation of an LC-MS/MS method for the determination of a novel thienoquinolin urea transporter inhibitor PU- 48 in rat plasma and its application to a pharmacokinetic study Biomedical chromatography : BMC 2018; 32-4.
[81]
Zhao Y, Li M, Li B, et al. Discovery and optimization of thienopyridine derivatives as novel urea transporter inhibitors. Eur J Med Chem 2019; 172: 131-42.
[http://dx.doi.org/10.1016/j.ejmech.2019.03.060] [PMID: 30959323]
[82]
Li M, Zhao Y, Zhang S, et al. A thienopyridine, CB-20, exerts diuretic activity by inhibiting urea transporters. Acta Pharmacol Sin 2019.
[http://dx.doi.org/10.1038/s41401-019-0245-5]
[83]
Lee S, Cil O, Diez-Cecilia E, Anderson MO, Verkman AS. Nanomolar-potency 1,2,4-triazoloquinoxaline inhibitors of the kidney urea transporter ut-a1. J Med Chem 2018; 61(7): 3209-17.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00343] [PMID: 29589443]
[84]
Klein JD, Sands JM. Urea transport and clinical potential of urearetics. Curr Opin Nephrol Hypertens 2016; 25(5): 444-51.
[http://dx.doi.org/10.1097/MNH.0000000000000252] [PMID: 27367911]
[85]
Esteva-Font C, Anderson MO, Verkman AS. Urea transporter proteins as targets for small-molecule diuretics. Nat Rev Nephrol 2015; 11(2): 113-23.
[http://dx.doi.org/10.1038/nrneph.2014.219] [PMID: 25488859]
[86]
Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007; 13(11): 1299-307.
[http://dx.doi.org/10.1038/nm1652] [PMID: 17922010]
[87]
Fadden P, Huang KH, Veal JM, et al. Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90. Chem Biol 2010; 17(7): 686-94.
[http://dx.doi.org/10.1016/j.chembiol.2010.04.015] [PMID: 20659681]

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