Expression of slc5a8 in Kidney and Its Role in Na+-coupled Transport of Lactate

Abstract

We report here on the expression of slc5a8 in kidney and its relevance to Na+-coupled reabsorption of lactate. slc5a8 is the murine ortholog of SLC5A8, a candidate tumor suppressor gene, which we recently cloned from human intestine and demonstrated its functional identity as a Na+-coupled transporter for short-chain fatty acids and lactate. The slc5a8 cDNA, cloned from mouse kidney, codes for a protein consisting of 611 amino acids. When expressed heterologously in mammalian cells or Xenopus oocytes, slc5a8 mediates Na+-coupled electrogenic transport of lactate/pyruvate as well as short-chain fatty acids (e.g. acetate, propionate, and butyrate). The Na+/fatty acid stoichiometry varies depending on the fatty acid substrate (2:1 for lactate and 4:1 for propionate). This phenomenon of variable Na+/substrate stoichiometry depending on the fatty acid substrate is also demonstrable with human SLC5A8. In situ hybridization with sagittal sections of mouse kidney demonstrates abundant expression of the transcripts in the cortex as well as the medulla. Brush border membrane vesicles prepared from rabbit kidney are able to transport lactate in a Na+-coupled manner. The transport process exhibits the overshoot phenomenon, indicating uphill lactate transport in response to the transmembrane Na+ gradient. The Na+-coupled lactate transport in these membrane vesicles is inhibitable by short-chain fatty acids. We conclude that slc5a8 is expressed abundantly in the kidney and that it plays a role in the active reabsorption of lactate. slc5a8 is the first transporter known to be expressed in mammalian kidney that has the ability to mediate the Na+-coupled reabsorption of lactate. We report here on the expression of slc5a8 in kidney and its relevance to Na+-coupled reabsorption of lactate. slc5a8 is the murine ortholog of SLC5A8, a candidate tumor suppressor gene, which we recently cloned from human intestine and demonstrated its functional identity as a Na+-coupled transporter for short-chain fatty acids and lactate. The slc5a8 cDNA, cloned from mouse kidney, codes for a protein consisting of 611 amino acids. When expressed heterologously in mammalian cells or Xenopus oocytes, slc5a8 mediates Na+-coupled electrogenic transport of lactate/pyruvate as well as short-chain fatty acids (e.g. acetate, propionate, and butyrate). The Na+/fatty acid stoichiometry varies depending on the fatty acid substrate (2:1 for lactate and 4:1 for propionate). This phenomenon of variable Na+/substrate stoichiometry depending on the fatty acid substrate is also demonstrable with human SLC5A8. In situ hybridization with sagittal sections of mouse kidney demonstrates abundant expression of the transcripts in the cortex as well as the medulla. Brush border membrane vesicles prepared from rabbit kidney are able to transport lactate in a Na+-coupled manner. The transport process exhibits the overshoot phenomenon, indicating uphill lactate transport in response to the transmembrane Na+ gradient. The Na+-coupled lactate transport in these membrane vesicles is inhibitable by short-chain fatty acids. We conclude that slc5a8 is expressed abundantly in the kidney and that it plays a role in the active reabsorption of lactate. slc5a8 is the first transporter known to be expressed in mammalian kidney that has the ability to mediate the Na+-coupled reabsorption of lactate. l-Lactate is present in blood at a concentration of ∼90 mg/liter (∼1.5 mm), but the urinary excretion of l-lactate is very low (100–600 mg/day). With the normal glomerular filtration rate of 120 ml/min, the fractional reabsorption rate for l-lactate in mammalian kidney is >95% (1Craig F.N. Am. J. Physiol. 1946; 146: 146-159Crossref PubMed Scopus (21) Google Scholar). The molecular identity of the transport system that is responsible for such an effective absorption process in the kidney has not yet been established. l-Lactate transport across mammalian cell plasma membrane is mediated by monocarboxylate transporters (MCTs) 1The abbreviations used are: MCT, monocarboxylate transporter; SMCT, sodium-coupled MCT; HRPE, human retinal pigment epithelial (cell line); Mes, 4-morpholineethanesulfonic acid; NIS, Na+/iodide symporter; PBS, phosphate-buffered saline. (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar). MCTs are H+-coupled transporters and, therefore, the direction of lactate flux in mammalian cells depends on the net chemical gradients for H+ and lactate across the membrane. The transport process is electroneutral because of the H+/lactate stoichiometry of 1:1. There are several members within the MCT gene family that are expressed differentially in different tissues (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar). Many of the MCT gene family members are expressed in the kidney (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar, 4Garcia C.K. Brown M.S. Pathak R.K. Goldstein J.L. J. Biol. Chem. 1995; 270: 1843-1849Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 5Friesema E.C.H. Ganguly S. Abdalla A. Fox J.E.M. Halestrap A.P. Visser T.J. J. Biol. Chem. 2003; 278: 40128-40135Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar), but the exact locations of these transporters in terms of cell type and the apical membrane versus the basolateral membrane of the tubular cells are not known. Because the lumen-facing brush border membrane of the renal tubular cells mediates the first step in the reabsorption of solutes present in the glomerular filtrate, been to the transport responsible for process Am. J. Physiol. Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, Biochem. J. PubMed Scopus Google Scholar). demonstrated that the renal brush border membrane a Na+-coupled transport system for is for the of H+-coupled l-lactate transport system in membrane Am. J. Physiol. Google Scholar). that MCTs not role in the first step in the reabsorption of l-lactate in the There is transport system expressed in mammalian tissues and known at the molecular that has the ability to mediate Na+-coupled transport of the molecular identity of the renal transport system that mediates the active reabsorption of l-lactate D. J. J. S. A. 2003; PubMed Scopus Google a candidate tumor suppressor gene that is by in human This gene codes for a transporter to the gene family known as the gene also that is a transporter but to the identity of the The expression of transporter in the and its role as a tumor suppressor to short-chain fatty acids as for fatty acids such as acetate, propionate, and are in the at by the of and J. Google Scholar, J.L. Biol. PubMed Scopus Google Scholar, Physiol. PubMed Scopus Google Scholar, Google Scholar). fatty acids are the for the J. Google Scholar, J.L. Biol. PubMed Scopus Google Scholar, Physiol. PubMed Scopus Google Scholar, Google Scholar). In cell and the of PubMed Scopus Google Scholar, A. J. Eur. J. PubMed Scopus Google Scholar, 2003; PubMed Scopus Google Scholar, 2003; PubMed Scopus Google Scholar). on these we recently the that be a Na+-coupled transporter for short-chain fatty acids S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). that mediate the Na+-coupled transport of the short-chain fatty acids acetate, propionate, and the transporter also has the ability to mediate Na+-coupled transport of Because the substrate of Na+-coupled transporter is to that of the we transporter the sodium-coupled monocarboxylate transporter The ability of to mediate Na+-coupled transport of l-lactate the as to transporter be responsible for the active reabsorption of l-lactate in the we the expression of transporter in mouse kidney by molecular in situ functional of the cloned murine and a of the functional of slc5a8 with of l-lactate transport in renal brush border membrane that is the transporter that is responsible for the active Na+-coupled reabsorption of l-lactate in mammalian from and from and from and and from of slc5a8 in from mouse The murine slc5a8 from by The of has been the the of slc5a8 in a The expression system used to the cloned mouse slc5a8 heterologously in the human retinal pigment epithelial cell as S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The of l-lactate and short-chain fatty acids in these cells The transport in and in in cells and in slc5a8 cells to for transport The transport by the transport in cells from the transport in of slc5a8 in Xenopus from cloned mouse slc5a8 the or from with of as The used for by the S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). with a and by the different fatty acids. The membrane at The the in the and of as the the step in membrane for a of in In the of the of the the substrate concentration for the of by the of the to a The Na+ of by the in the of of The from these by the to the the of Na+ in the The the by and by of for l-lactate and in different as S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Am. J. Physiol. 278: Google Scholar, S. Biochem. J. 2004; PubMed Scopus Google Scholar). the of the the expression of expression of are We that the of expression of slc5a8 from the for of the transport process but not for the of the we the of the murine slc5a8 by and the expression The by S. of the of the Xenopus gene of the these are known to be expressed in at 1995; PubMed Scopus Google Scholar, S. A. PubMed Scopus Google Scholar). The with l-lactate or and a of the of the the of l-lactate and the by the with the The within the the the and to the the with l-lactate and The for substrate and used to the of the slc5a8 in The of mouse slc5a8 by the and and as the by the to the of the for the of The first in a and the by The with and used for the of the slc5a8 The to the of the with cells with and transport in in In of at with The are as of these the of from different tissues of mouse used to the expression of slc5a8 transcripts in This not from intestine or We prepared a with from mouse intestine and with a for mouse In sections of mouse in at and in in PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), sections in and with prepared in to of the with in for The by the in in in PBS, in and for at in with the acid and with the and at The sections in at in at and in at of the sections in a acid and and with the The to and with for at in the for and with a and The in in and to but not that the of a be in the In with the to the of and a of mouse slc5a8 by and the and the of the by The used for and which to and in mouse slc5a8 We the of the for slc5a8 by the with the of the by the as the The prepared by in with for the and for the the with for the and for the of l-Lactate in Brush border membrane vesicles prepared from rabbit kidney cortex by the as Biochem. J. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar). The membrane vesicles with The protein concentration of the membrane to of in these membrane vesicles by the filtration Biochem. J. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar). by membrane with of The in When in the of the by with an concentration of in and the with different membrane of slc5a8 mouse slc5a8 is and codes for a protein consisting of 611 amino acids. The has been the of the amino acid transmembrane in the protein with the amino at the of the membrane and the at the of the membrane. With mouse slc5a8 has transmembrane and The amino acid of mouse slc5a8 is to that of human SLC5A8. also to that of sodium-coupled and sodium-coupled transporter The identity is with mouse and with mouse The amino acid from the mouse is to the that in the as an protein on the mouse of slc5a8 in that slc5a8 transcripts are in the and kidney in mouse There is expression of the transporter in the and There are different transcripts and transcripts are expressed in in the kidney, the and transcripts are in the and of slc5a8 in a the transport of the cloned mouse we first used a mammalian cell expression We expressed the in cells the expression and the of l-lactate in cells and in cells The of l-lactate in cells in The The l-lactate by with at We the transport of different as well as the and the the The of acetate, propionate, and in cells mouse slc5a8 in cells with In the of and not different the cells and the that the cloned mouse slc5a8 is of The of mouse slc5a8 by l-lactate in cells and in cells in the or of The of l-lactate in cells mouse slc5a8 in cells in the of the l-lactate not in the of and to for Na+ in the process mediated by mouse We also the of the transporter with acetate, propionate, and and the that the of these mediated by mouse slc5a8 also on the of Na+ not of by mouse in a of slc5a8 to the substrate of slc5a8 to that of we the of a of MCTs (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar), on the transport of We the of l-lactate and in cells and cells in in the and of acid In the of the MCT the expression of slc5a8 the of l-lactate by the not l-lactate mediated by it the transport of slc5a8 to a In the of the the of l-lactate in cells with phenomenon with as the In the of the of in cells in the the of in cells in We the ability of short-chain fatty acids to l-lactate in the of the MCT short-chain fatty acids propionate, and the of l-lactate slc5a8 a concentration of the with and the of l-lactate transport by short-chain fatty acids in the of fatty in a of in cells with transport for We the of to is mediated by MCTs or SLC5A8. The of and l-lactate in cells with the in the of Na+ and in the of l-lactate the in the of Na+ and in the of The process on with at the of inhibitable by l-lactate at and at that monocarboxylate transport in cells is mediated by MCTs by SLC5A8. We to these cells not The that these cells but at used as a in these that is of to monocarboxylate transport in of slc5a8 in the the mammalian cell expression system that the cloned mouse slc5a8 is able to transport l-lactate and in a the This low it to of the transport we the expression that the of in with mouse slc5a8 in not We used the to the transport of mouse of to l-lactate and the the with which to the of depending on the substrate at a concentration of substrate l-Lactate and the by and with the as the of the fatty acid The transporter not with is The and the not as not the cloned mouse slc5a8 is for l-lactate and short-chain The by l-lactate the Na+ When Na+ with the not indicating the for Na+ in the transport There of because the the or The by With l-lactate as the the with a of at The a with Na+ concentration the for the of the transport process by Na+ We also the with as the The by with a of at The a with Na+ concentration the for the of the transport process by Na+ Because l-lactate and as the the of Na+ in the transport process the molecular for the electrogenic of the transport We the for acetate, and at by the of with of these the for the transporter with a of The for and for The of the by the of slc5a8 on the membrane as from the The as the membrane With as the we the of membrane on not The by with of the membrane. The for at and the to at This that the membrane as an for the transport The for for also by membrane The for at and the as the membrane and as the membrane This that the substrate of the transporter is by membrane to a The for the not by membrane The at the membrane of to We also the of of the on There and in terms of not and for mouse in the Xenopus expression system with as the are for at a of an and a in different oocytes, and the from the used for Na+ in different oocytes, and the from the are as of on membrane for acetate, propionate, and at a concentration of of prepared from a the in by of In we these to be low to to the Because the of with for of substrate and we to of to a of in to a of substrate within the used to the With these low of the we to the of slc5a8 in a different in an to the expression of the we 1995; PubMed Scopus Google Scholar, S. A. PubMed Scopus Google Scholar). We first the of lactate in with prepared from and The in The in with from the in with from We the by of l-lactate in these There in with In with from cDNA, the of the by l-lactate in with from we an of the for slc5a8 in with prepared from With different oocytes, the for l-lactate This well with the from the Na+ which a of for the The that the stoichiometry is With the transport process is to be with the of l-lactate a of Because the for the of also we the for to a to that with the for not The a stoichiometry of This an not because the for the of to that for but also because the Na+/substrate depending on the the for with the we recently for human S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). we not the for human with l-lactate as the substrate in we to the varies depending on the substrate in the of human SLC5A8. This to the of the for human for l-lactate and The for l-lactate and for and that the in the is not for mouse phenomenon is also with human SLC5A8. of slc5a8 in from the slc5a8 transcripts are expressed in the kidney and the the of slc5a8 expression in the kidney, we in situ hybridization sagittal sections of mouse kidney with the the kidney, with expression in the cortex as well as in the The hybridization with the because the not and of the and it that the expression to tubular epithelial The hybridization in the cortex in the medulla. The of the in the cortex that the transporter is expressed in the The of the in the cortex as well as in the that the transporter is expressed not in the of the but also in the of the and in the of of l-Lactate in Brush of l-lactate has been in renal brush border membrane vesicles in several Am. J. Physiol. Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, Biochem. J. PubMed Scopus Google Scholar). that renal reabsorption of l-lactate across the tubular epithelial apical membrane a Na+-coupled is very in the the substrate of transport and been to the l-lactate transport system in the kidney brush border membrane Am. J. Physiol. Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, Biochem. J. PubMed Scopus Google Scholar). Because slc5a8 is a Na+-coupled transporter not for l-lactate but also for short-chain fatty acids such as acetate, propionate, and it be of to the Na+-coupled l-lactate transport system in the renal brush border membrane with these short-chain fatty acids. we l-lactate in rabbit renal brush border membrane vesicles prepared from kidney The of l-lactate in these membrane vesicles The of an Na+ the by In the of a Na+ l-lactate the overshoot phenomenon, the at a the with a When Na+ in the with the very low and the The Na+-coupled l-lactate by as well as by short-chain fatty acids a concentration of acetate, propionate, and the of l-lactate by that l-lactate the of l-lactate with an of The for by and and that the Na+-coupled transport system for l-lactate in renal brush border membrane vesicles short-chain fatty acids as the and substrate of the system in the kidney brush border membrane are to of the cloned This is the first report of the molecular identity of the Na+-coupled l-lactate transporter expressed in mammalian This is the transporter that is present in the mammalian it in the Na+-coupled absorption of short-chain fatty acids D. J. J. S. A. 2003; PubMed Scopus Google Scholar, S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We transporter for sodium-coupled monocarboxylate transporter because its substrate is to that of The of MCTs acetate, propionate, and (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar). of these are also for the cloned mouse The MCTs and is in the of the MCTs are to a transmembrane H+ is to a transmembrane Na+ gradient. The stoichiometry for the different for MCTs and MCTs mediate the H+-coupled transport of an with a stoichiometry of (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar), mediates the Na+-coupled transport of an electrogenic with a variable stoichiometry depending on the monocarboxylate the in substrate and has to and MCTs to different gene the a of the gene family the gene Pflugers Arch. Eur. J. Physiol. 2004; 447: PubMed Scopus Google Scholar), the are members of the gene family (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar). MCTs and is MCTs are expressed in mammalian cells (2Halestrap A.P. Price N.T. Biochem. J. 1999; 343: 281-299Crossref PubMed Scopus (1100) Google Scholar, 3Halestrap A.P. Meredith D. Pflugers Arch. Eur. J. Physiol. 2004; 447: 619-628Crossref PubMed Scopus (829) Google Scholar), the expression of is to the kidney and the The abundant expression of in the kidney its as a transporter responsible for the Na+-coupled active reabsorption of In the the for the transporter are the short-chain fatty acids acetate, propionate, and by of There is for the expression of in the apical membrane of epithelial cells J. PubMed Scopus Google Scholar, J. 2004; PubMed Scopus Google Scholar). functional that the transporter plays a role in the transport of in these a which to the of the transporter as apical J. PubMed Scopus Google Scholar, J. 2004; PubMed Scopus Google Scholar). we not transport human S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google or mouse not cloned in The for the are not known. on the electrogenic of the Na+-coupled l-lactate transport process in mammalian kidney with for the of the transport process Am. J. Physiol. Google Scholar, J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar), for the electroneutral of the transport process J. Biol. Chem. Full Text PDF PubMed Google Scholar). with the cloned that the transport process is the stoichiometry varies depending on the The for stoichiometry is for l-lactate and 4:1 for This variable stoichiometry is not from the of Na+ of The for the from these for l-lactate as well as The not the of Na+ in the transport the for the transport of a the Na+-coupled transporters and is but the transport process is with the of at Na+ in the transport process Am. J. Physiol. 278: Google Scholar, J. Biol. PubMed Scopus Google Scholar). the variable stoichiometry of mouse and human SMCT, depending on the is The l-lactate and is the The or of the to the of the transporter protein of the and such in the the in Na+ has to be that the exact of of the and is not known. the for Na+/substrate stoichiometry for by of the of the monocarboxylate and the of that of Na+ be to these The that in the mammalian cell expression system but not in the expression system are The of on the of in the mammalian cell expression system the membrane the is not these in the to the in the of the expression the of on in mammalian cells be to in by in In to mammalian are to in in response to in is also that on the of SMCT, depending on the cell type used for the the transporter is by in a mammalian cell expression system an cell but has on the of the transporter in the Xenopus expression system C.K. Am. J. Physiol. PubMed Google Scholar). it is that the transport is by these a This be to the role of a transmembrane H+ as an for the transport process that the the transport in Xenopus as by the acid has a of and, therefore, in the in the Because an is to the concentration of the these be by in the concentration of the for is that a for H+ on its a be in the in renal tubular cell and in renal brush border membrane vesicles by the of on the transport of in its is to that the of the in the of the is to the of H+ a of the of the of on these The of by in mammalian cells expression of the cloned transporter that reabsorption of lactate in the renal is by the of This that be a functional and the in the are to these of transport that and with propionate, and at a concentration of substrate that these are not to in the substrate because the for and l-lactate are the in by in the by these This is by the from membrane When at a concentration for the ability of short-chain fatty acids to the of and are as effective as l-lactate and In situ hybridization that is at in the mouse kidney, in the cortex as well as the medulla. the hybridization are in the cortex in the are present the kidney, indicating that the transporter is expressed in of the are because in kidney that the absorption of lactate in the Full Text PDF PubMed Scopus Google Scholar). 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The of an reabsorption for these in the kidney in the Because is also expressed in the the of short-chain fatty acids as as in the J. Google Scholar, J.L. Biol. PubMed Scopus Google Scholar, Physiol. PubMed Scopus Google Scholar, Google Scholar), the ability of the transporter to transport these fatty acids be of in the in the The effective concentration of these fatty acids to the on cells is in the of is present in blood at to J.L. Full Text PDF PubMed Scopus Google Scholar). Because the of these fatty acids are in the in the the of these fatty acids are to be on the of the epithelial in the blood because of effective absorption of these fatty acids The of the in the with cells in the the cell the cells in the are to be to of short-chain fatty acids the cells in the The of and in cells with short-chain fatty acids in the relevance to and to and fatty acids in the been to be in the for and PubMed Scopus Google Scholar, A. J. Eur. J. 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