Abstract
Urea movement across plasma membranes is modulated by specialized urea transporter proteins. These proteins are proposed to play key roles in the urinary concentrating mechanism and fluid homeostasis. To date, two urea-transporter genes have been cloned; UT-A (Slc14a2), encoding at least five proteins and UT-B (Slc14a1) encoding a single protein isoform. Recently we engineered mice that lack the inner medullary collecting duct (IMCD) urea transporters, UT-A1 and UT-A3 (UT-A1/3 −/− mice). This article includes 1) a historical review of the role of renal urea transporters in renal function; 2) a review of our studies utilizing the UT-A1/3 −/− mice; 3) description of an additional line of transgenic mice in which beta-galactosidase expression is driven by the alpha-promoter of the UT-A gene, which is allowing better physiological definition of control mechanisms for UT-A expression; and 4) a discussion of the implications of the studies in transgenic mice for the teaching of kidney physiology.
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References
Atherton J.C., Hai M.A., Thomas S. 1968. Effects of water diuresis and osmotic (mannitol) diuresis on urinary solute excretion by the conscious rat. J. Physiol. 197:395–410
Bagnasco S.M., Peng T., Nakayama Y., Sands J.M. 2000. Differential expression of individual UT-A urea transporter isoforms in rat kidney. J. Am. Soc. Nephrol. 11:1980–1986
Bankir L., Ahloulay M., Bouby N., Trinh-Trang-Tan M.M., Machet F., Lacour B., Jungers P. 1993. Is the process of urinary urea concentration responsible for a high glomerular filtration rate? J. Am. Soc. Nephrol. 4:1091–1103
Bankir L., Bouby N., Trinh-Trang-Tan M.M. 1991. Vasopressin-dependent kidney hypertrophy: role of urinary concentration in protein-induced hypertrophy and in the progression of chronic renal failure. Am. J. Kidney Dis. 17:661–665
Bankir L., Chen K., Yang B. 2004. Lack of UT-B in vasa recta and red blood cells prevents urea-induced improvement of urinary concentrating ability. Am. J. Physiol. 286:F144–F151
Berger S., Bleich M., Schmid W., Cole T.J., Peters J., Watanabe H., Kriz W., Warth R., Greger R., Schutz G. 1998. Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc. Natl. Acad. Sci. USA 95:9424–9429
Berliner R.W., Bennett C.M. 1967. Concentration of urine in the mammalian kidney. Am. J. Med. 42:777–789
Berliner R.W., Levinsky N.G., Davidson D.G., Eden M. 1958. Dilution and concentration of the urine and the action of antidiuretic hormone. Am. J. Med. 24:730–744
Chou C.L., Knepper M.A. 1989. Inhibition of urea transport in inner medullary collecting duct by phloretin and urea analogues. Am. J. Physiol. 257:F359–F365
Chou C.L., Sands J.M., Nonoguchi H., Knepper M.A. 1990a. Concentration dependence of urea and thiourea transport in rat inner medullary collecting duct. Am. J. Physiol. 258:F486–F494
Chou C.L., Sands J.M., Nonoguchi H., Knepper M.A. 1990b. Urea gradient-associated fluid absorption with sigma urea = 1 in rat terminal collecting duct. Am. J. Physiol. 258:F1173–F1180
Clapp J.R. 1965. Urea reabsorption by the proximal tubule of the dog. Proc. Soc. Exp. Biol. Med. 120:521–523
Clapp J.R. 1966. Renal tubular reabsorption of urea in normal and protein-depleted rats. Am. J. Physiol. 210:1304–1308
Dicker S.E. 1949. Effect of the protein content of the diet on the glomerular filtration rate of young and adult rats. J. Physiol. 108:197–202
DiGiovanni S.R., Nielsen S., Christensen E.I., Knepper M.A. 1994. Regulation of collecting duct water channel expression by vasopressin in Brattleboro rat. Proc. Natl. Acad. Sci. USA 91:8984–8988
Ecelbarger C.A., Terris J., Frindt G., Echevarria M., Marples D., Nielsen S., Knepper M.A. 1995. Aquaporin-3 water channel localization and regulation in rat kidney. Am. J. Physiol. 269:F663–672
Fenton R.A., Chou C.L., Ageloff S., Brandt W., Stokes J.B., Knepper M.A. 2003. Increased collecting duct urea transporter expression in Dahl salt- sensitive rats. Am. J. Physiol. 285:F143–F151
Fenton R.A., Chou C.L., Stewart G.S., Smith C.P., Knepper M.A. 2004. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc. Natl. Acad. Sci. USA 101:7469–7474
Fenton R.A., Cooper G.J., Morris I.D., Smith C.P. 2002a. Coordinated expression of UT-A and UT-B urea transporters in rat testis. Am. J. Physiol. 282:C1492–C1501
Fenton R.A., Cottingham C.A., Stewart G.S., Howorth A., Hewitt J.A., Smith C.P. 2002b. Structure and characterization of the mouse UT-A gene (Slc14a2). Am. J. Physiol. 282:F630–F638
Fenton R.A., Flynn A., Shodeinde A., Smith C.P., Schnermann J., Knepper M.A. 2005. Renal phenotype of UT-A urea transporter knockout mice. J. Am. Soc. Nephrol. 16:1583–1592
Fenton R.A., Howorth A., Cooper G.J., Meccariello R., Morris I.D., Smith C.P. 2000. Molecular characterization of a novel UT-A urea transporter isoform (UT- A5) in testis. Am. J. Physiol. 279:C1425–C1431
Fenton R.A., Shodeinde A., Knepper M.A. 2006. UT-A urea transporter promoter, UT-Aα, targets principal cells of the renal inner medullary collecting duct. Am. J. Physiol. 290:F188–F195
Fenton R.A., Stewart G.S., Carpenter B., Howorth A., Potter E.A., Cooper G.J., Smith C.P. 2002c. Characterization of mouse urea transporters UT-A1 and UT-A2. Am. J. Physiol. 283:F817–F825
Gamble J.L., McKhann C.F., Butler A.M., Tuthill E. 1934. An economy of water in renal function referable to urea. Am. J. Physiol. 109:139–154
Gamble J.L., Putnam M.C., McKhann C.F. 1929. The optimal water requirement in renal function. Am. J. Physiol. 88:571–580
Grantham J.J., Burg M.B. 1966. Effect of vasopressin and cyclic AMP on permeability of isolated collecting tubules. Am. J. Physiol. 211:255–259
Hummler E., Barker P., Talbot C., Wang Q., Verdumo C., Grubb B., Gatzy J., Burnier M., Horisberger J.D., Beermann F., Boucher R., Rossier B.C. 1997. A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism. Proc. Natl. Acad. Sci. USA 94:1710–1715
Imai M., Kokko J.P. 1974. Sodium chloride, urea, and water transport in the thin ascending limb of Henle. Generation of osmotic gradients by passive diffusion of solutes. J. Clin. Invest. 53:393–402
Jamison R.L., Bennett C.M., Berliner R.W. 1967. Countercurrent multiplication by the thin loops of Henle. Am. J. Physiol. 212:357–366
Karakashian A., Timmer R.T., Klein J.D., Gunn R.B., Sands J.M., Bagnasco S.M. 1999. Cloning and characterization of two new isoforms of the rat kidney urea transporter: UT-A3 and UT-A4. J. Am. Soc. Nephrol. 10:230–237
Kato A., Sands J.M. 1998. Evidence for sodium-dependent active urea secretion in the deepest subsegment of the rat inner medullary collecting duct. J. Clin. Invest. 101:423–428
Kato A., Sands J.M. 1999. Urea transport processes are induced in rat IMCD subsegments when urine concentrating ability is reduced. Am. J. Physiol. 276:F62–71
Kawamura S., Kokko J.P. 1976. Urea secretion by the straight segment of the proximal tubule. J. Clin. Invest. 58:604–612
Klumper J.D., Ullrich K.J., Hilger H.H. 1958. [Content of urea in collecting tubules of mammalian kidney.]. Pfluegers Arch. 267:238–243
Knepper M.A. 1983. Urea transport in nephron segments from medullary rays of rabbits. Am. J. Physiol. 244:F622–F627
Knepper M.A., Chou C.L., Layton H.E. 1993. How is urine concentrated by the renal inner medulla? Contrib. Nephrol. 102:144–160
Knepper M.A., Danielson R.A., Saidel G.M., Post R.S. 1977. Quantitative analysis of renal medullary anatomy in rats and rabbits. Kidney Int. 12:313–323
Knepper M.A., Roch-Ramel F. 1987. Pathways of urea transport in the mammalian kidney. Kidney Int. 31:629–633
Knepper M.A., Saidel G.M., Hascall V.C., Dwyer T. 2003. Concentration of solutes in the renal inner medulla: interstitial hyaluronan as a mechano-osmotic transducer. Am. J. Physiol. 284:F433–F446
Knepper M.A., Sands J.M., Chou C.L. 1989. Independence of urea and water transport in rat inner medullary collecting duct. Am. J. Physiol. 256:F610–F621
Knepper M.A., Star R.A. 1990. The vasopressin-regulated urea transporter in renal inner medullary collecting duct. Am. J. Physiol. 259:F393–F401
Kokko J.P., Rector F.C. 1972. Countercurrent multiplication system without active transport in inner medulla. Kidney Int. 2:214–223
Kondo Y., Abe K., Igarashi Y., Kudo K., Tada K., Yoshinaga K. 1993. Direct evidence for the absence of active Na+ reabsorption in hamster ascending thin limb of Henle’s loop. J. Clin. Invest. 91:5–11
Kuhn W., Ramel A. 1959. Activer Salztransport als moeglicher (und wahrscheinlicher) Einzeleffekt bei der Harnkonzentrierung in der Niere. Helv. Chim. Acta. 42:628–660
Lassiter W.E., Gottschalk C.W., Mylle M. 1961. Micropuncture study of net transtubular movement of water and urea in nondiuretic mammalian kidney. Am. J. Physiol. 200:1139–1147
Lassiter W.E., Mylle M., Gottschalk C.W. 1966. Micropuncture study of urea transport in rat renal medulla. Am. J. Physiol. 210:965–970
Lucien N., Sidoux-Walter F., Olives B., Moulds J., Le Pennec P.Y., Cartron J.P., Bailly P. 1998. Characterization of the gene encoding the human Kidd blood group/urea transporter protein. Evidence for splice site mutations in Jknull individuals. J. Biol. Chem. 273:12973–12980
Macey R.I., Farmer R.E. 1970. Inhibition of water and solute permeability in human red cells. Biochem. Biophys. Acta. 211:104–106
Mackay E.M., Mackay L.L., Addis T. 1928. Factors which determine renal weight. V. The protein intake. Am. J. Physiol. 86:459–465
Morgan T., Berliner R.W. 1968. Permeability of the loop of Henle, vasa recta, and collecting duct to water, urea, and sodium. Am. J. Physiol. 215:108–115
Morgan T., Sakai F., Berliner R.W. 1968. In vitro permeability of medullary collecting ducts to water and urea. Am. J. Physiol. 214:574–581
Nakayama Y., Naruse M., Karakashian A., Peng T., Sands J.M., Bagnasco S.M. 2001. Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter. Biochim. Biophys. Acta. 1518:19–26
Naruse M., Klein J.D., Ashkar Z.M., Jacobs J.D., Sands J.M. 1997. Glucocorticoids downregulate the vasopressin-regulated urea transporter in rat terminal inner medullary collecting ducts. J. Am. Soc. Nephrol. 8:517–523
Nielsen S., Knepper M.A. 1993. Vasopressin activates collecting duct urea transporters and water channels by distinct physical processes. Am. J. Physiol. 265:F204–F213
Nielsen S., Terris J., Smith C.P., Hediger M.A., Ecelbarger C.A., Knepper M.A. 1996. Cellular and subcellular localization of the vasopressin- regulated urea transporter in rat kidney. Proc. Natl. Acad. Sci. USA 93:5495–5500
Olives B., Neau P., Bailly P., Hediger M.A., Rousselet G., Cartron J.P., Ripoche P. 1994. Cloning and functional expression of a urea transporter from human bone marrow cells. J. Biol. Chem. 269:31649–31652
Peng T., Sands J.M., Bagnasco S.M. 2002. Glucocorticoids inhibit transcription and expression of the UT-A urea transporter gene. Am. J. Physiol. 282:F853–F858
Promeneur D., Rousselet G., Bankir L., Bailly P., Cartron J.P., Ripoche P., Trinh-Trang-Tan M.M. 1996. Evidence for distinct vascular and tubular urea transporters in the rat kidney. J. Am. Soc. Nephrol. 7:852–860
Sands J.M. 2003. Mammalian Urea Transporters. Annu. Rev. Physiol. 65: 543–566
Sands J.M., Knepper M.A. 1987. Urea permeability of mammalian inner medullary collecting duct system and papillary surface epithelium. J. Clin. Invest. 79:138–147
Sands J.M., Nonoguchi H., Knepper M.A. 1987. Vasopressin effects on urea and H2O transport in inner medullary collecting duct subsegments. Am. J. Physiol. 253:F823–F832
Schmidt-Nielsen B. 1955. Urea excretion in white rats and kangaroo rats as influenced by excitement and by diet. Am. J. Physiol. 181:131–139
Schmidt-Nielsen B. 1995. August Krogh Lecture. The renal concentrating mechanism in insects and mammals: a new hypothesis involving hydrostatic pressures. Am. J. Physiol. 268:R1087–1100
Seney F.D. Jr., Persson E.G., Wright F.S. 1987. Modification of tubuloglomerular feedback signal by dietary protein. Am. J. Physiol. 252:F83–F90
Seney F.D. Jr., Wright F.S. 1985. Dietary protein suppresses feedback control of glomerular filtration in rats. J. Clin. Invest. 75:558–568
Shannon J.A. 1936. Glomerular filtration and urea excretion in relation to urine flow in the dog. Am. J. Physiol. 117:206–225
Shannon J.A. 1938. Urea excretion in the normal dog during forced diuresis. Am. J. Physiol. 122:782–787
Shayakul C., Knepper M.A., Smith C.P., DiGiovanni S.R., Hediger M.A. 1997. Segmental localization of urea transporter mRNAs in rat kidney. Am. J. Physiol. 272:F654–660
Shayakul C., Steel A., Hediger M.A. 1996. Molecular cloning and characterization of the vasopressin-regulated urea transporter of rat kidney collecting ducts. J. Clin. Invest. 98:2580–2587
Smith C.P., Lee W.S., Martial S., Knepper M.A., You G., Sands J.M., Hediger M.A. 1995. Cloning and regulation of expression of the rat kidney urea transporter (rUT2). J. Clin. Invest. 96:1556–1563
Smith C.P., Potter E.A., Fenton R.A., Stewart G.S. 2004. Characterization of a human colonic cDNA encoding a structurally novel urea transporter, hUT-A6. Am. J. Physiol. 287:C1087–C1093
Star R.A., Nonoguchi H., Balaban R., Knepper M.A. 1988. Calcium and cyclic adenosine monophosphate as second messengers for vasopressin in the rat inner medullary collecting duct. J. Clin. Invest. 81:1879–1888
Stephenson J.L. 1972. Concentration of urine in a central core model of the renal counterflow system. Kidney Int. 12:85–94
Stewart G.S., Fenton R.A., Wang W., Kwon T.H., White S.J., Collins V.M., Cooper G., Nielsen S., Smith C.P. 2004. The basolateral expression of mUT-A3 in the mouse kidney. Am. J. Physiol. 286:F979–F987
Terris J.M., Knepper M.A., Wade J.B. 2001. UT-A3: localization and characterization of an additional urea transporter isoform in the IMCD. Am. J. Physiol. 280:F325–F332
Thomas S.R. 2000. Inner medullary lactate production and accumulation: a vasa recta model. Am. J. Physiol. 279:F468–F481
Timmer R.T., Klein J.D., Bagnasco S.M., Doran J.J., Verlander J.W., Gunn R.B., Sands J.M. 2001. Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues. Am. J. Physiol. 281:C1318–C1325
Trinh-Trang-Tan M.M., Bankir L. 1998. Integrated function of urea transporters in the mammalian kidney. Exp. Nephrol. 6:471–479
Tsukaguchi H., Shayakul C., Berger U.V., Tokui T., Brown D., Hediger M.A. 1997. Cloning and characterization of the urea transporter UT3: localization in rat kidney and testis. J. Clin. Invest. 99:1506–1515
Uchida S., Sohara E., Rai T., Ikawa M., Okabe M., Sasaki S. 2005. Impaired urea accumulation in the inner medulla of mice lacking the urea transporter UT-A2. Mol. Cell. Biol. 25:7357–7363
Ullrich K.J., Drenckhan F.O., Jarausch K.H. 1955. Untersuchungen zum Problem der Harnkonzentrierung und Verdћnnung. Uber das osmotische Verhalten von Nierenzellen und die begleitende Elektrolytanh≜ufung im Nierengewebe bei verschiedenen Diuresezust≜nden. Pfluegers Arch. 261:62–77
Ullrich K.J., Jarausch K.H. 1956. Untersuchungen zum Problem der Harnkonzentrierung und Harnverdћnnung. Pfluegers Arch. 262:S537–550
Wade J.B., Lee A.J., Liu J., Ecelbarger C.A., Mitchell C., Bradford A.D., Terris J., Kim G.H., Knepper M.A. 2000. UT-A2: a 55-kDa urea transporter in thin descending limb whose abundance is regulated by vasopressin. Am. J. Physiol. 278:F52–F62
Wall S.M., Han J.S., Chou C.-L., Knepper M.A. 1992. Kinetics of urea and water permeability activation by vasopressin in rat terminal IMCD. Am. J. Physiol. 262:989–998
Wang X.Y., Beutler K., Nielsen J., Nielsen S., Knepper M.A., Masilamani S. 2002. Decreased abundance of collecting duct urea transporters UT-A1 and UT-A3 with ECF volume expansion. Am. J. Physiol. 282:F577–F584
Xu Y., Olives B., Bailly P., Fischer E., Ripoche P., Ronco P., Cartron J.P., Rondeau E. 1997. Endothelial cells of the kidney vasa recta express the urea transporter HUT11. Kidney Int. 51:138–146
Yang B., Bankir L. 2005. Urea and urine concentrating ability: new insights from studies in mice. Am. J. Physiol. 288:F881–F896
Yang B., Verkman A.S. 2002. Analysis of double knockout mice lacking aquaporin-1 and urea transporter UT-B. Evidence for UT-B-facilitated water transport in erythrocytes. J. Biol. Chem. 277:36782–36786
You G., Smith C.P., Kanai Y., Lee W.S., Stelzner M., Hediger M.A. 1993. Cloning and characterization of the vasopressin-regulated urea transporter. Nature 365:844–847
Yun J., Schoneberg T., Liu J., Schulz A., Ecelbarger C.A., Promeneur D., Nielsen S., Sheng H., Grinberg A., Deng C., Wess J. 2000. Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene. J. Clin. Invest. 106:1361–1371
Acknowledgment
The work described in this paper was supported in part by the Intramural Budget of the National Heart, Lung and Blood Institute (Project ZO1-HL-01282-KE) to M. A. Knepper. The Water and Salt Research Center at the University of Aarhus is established and supported by the Danish National Research Foundation (Danmarks Grundforskningsfond). R. A. Fenton is supported by the Carlsberg Foundation (Carlsbergfondet), the Nordic Council (the Nordic Centre of Excellence Programme in Molecular Medicine) and the Danish National Research Foundation. C. P. Smith is supported by The Royal Society and the BBSRC.
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Fenton, R.A., Smith, C. & Knepper, M. Role of Collecting Duct Urea Transporters in the Kidney – Insights from Mouse Models. J Membrane Biol 212, 119–131 (2006). https://doi.org/10.1007/s00232-006-0871-y
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DOI: https://doi.org/10.1007/s00232-006-0871-y