Renal localization and regulation by dietary phosphate of the MCT14 orphan transporter

PLOS ONE, Dec 2019

MCT14 is an orphan transporter belonging to the SLC16 transporter family mediating the transport of monocarboxylates, aromatic amino acids, creatine, and thyroid hormones. The expression, tissue localization, regulation, and function of MCT14 are unknown. In mouse MCT14 mRNA abundance is highest in kidney. Using a newly developed and validated antibody, MCT14 was localized to the luminal membrane of the thick ascending limb of the loop of Henle colocalizing in the same cells with uromodulin and NKCC2. MCT14 mRNA and protein was found to be highly regulated by dietary phosphate intake in mice being increased by high dietary phosphate intake at both mRNA and protein level. In order to identify the transport substrate(s), we expressed MCT14 in Xenopus laevis oocytes where MCT14 was integrated into the plasma membrane. However, no transport was discovered for the classic substrates of the SLC16 family nor for phosphate. In summary, MCT14 is an orphan transporter regulated by phosphate and highly enriched in kidney localizing to the luminal membrane of one specific nephron segment.

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Renal localization and regulation by dietary phosphate of the MCT14 orphan transporter

June Renal localization and regulation by dietary phosphate of the MCT14 orphan transporter Thomas KnoÈ pfel 0 1 Alexander Atanassoff 0 1 Nati Hernando 0 1 JuÈ rg Biber 0 1 Carsten A. Wagner 0 1 0 Institute of Physiology, University of Zurich , Zurich, Switzerland, 2 NCCR Kidney.CH , Switzerland 1 Editor: Nick Ashton, The University of Manchester , UNITED KINGDOM MCT14 is an orphan transporter belonging to the SLC16 transporter family mediating the transport of monocarboxylates, aromatic amino acids, creatine, and thyroid hormones. The expression, tissue localization, regulation, and function of MCT14 are unknown. In mouse MCT14 mRNA abundance is highest in kidney. Using a newly developed and validated antibody, MCT14 was localized to the luminal membrane of the thick ascending limb of the loop of Henle colocalizing in the same cells with uromodulin and NKCC2. MCT14 mRNA and protein was found to be highly regulated by dietary phosphate intake in mice being increased by high dietary phosphate intake at both mRNA and protein level. In order to identify the transport substrate(s), we expressed MCT14 in Xenopus laevis oocytes where MCT14 was integrated into the plasma membrane. However, no transport was discovered for the classic substrates of the SLC16 family nor for phosphate. In summary, MCT14 is an orphan transporter regulated by phosphate and highly enriched in kidney localizing to the luminal membrane of one specific nephron segment. Data Availability Statement; All relevant data are within the paper - Funding: This work was funded by the National Center for Excellence in Research NCCR Kidney. CH was financed by the Swiss National Science Foundation to JB and CAW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction Inorganic phosphate is a molecule involved in energy metabolism and signaling as well as essential for structural molecules in cells and bone. Phosphate excess triggers ectopic calcifications and is associated with increased cardiovascular mortality. Therefore, the plasma levels of phosphate are kept in a close range; this is achieved by a variety of compensatory and highly regulated mechanisms. Phosphate deficiency leads to increased levels of plasma active vitamin D, which promotes intestinal phosphate absorption at least in part by stimulating the expression of the Na+-dependent phosphate transporter NaPi-IIb [ 1 ]. Additionally, hypophosphatemia blunts the production of parathyroid hormone (PTH) [ 2 ] and fibroblast growth factor 23 (FGF23) [ 3 ], releasing the inhibitory effect of both hormones on renal phosphate cotransporters (NaPi-IIa, NaPi-IIc and PiT-2), thus enhancing renal reabsorption of phosphate. On the other hand hyperphosphatemia leads to an increased renal excretion of phosphate, an effect mediated at least in part by PTH [ 2 ] and FGF23 [ 4,5,6 ]. Both hormones reduce the renal expression of NaPi-IIa NaPi-IIc and PiT-2 in the proximal tubule [ 2 ], and FGF23 additionally suppresses the production of vitamin D[ 7 ]. But beyond these effects directly linked to phosphate metabolism, alterations in phosphate intake affect, among other effects, glycogenolysis and glucose production [ 8 ], indicating broader systemic changes in response to phosphate status. The SLC16 gene family comprises 14 members collectively called MCTs (monocarboxylate transporter) due to the fact that the first 4 members to be characterized mediate transport of monocarboxylates such as lactate, pyruvate and ketone bodies, in a proton dependent manner [ 9 ]. MCT1, 3 and 4 associate with CD147 (basigin) [ 10 ], an immunoglobulin-like protein, that acts as a chaperone for these MCTs. The interaction of MCT1 and CD147 has been extensively studied and it was shown that sorting of MCT1 to the right pole of an epithelial cell relies on CD147 [ 11 ]. MCT1 and 2 are both expressed in kidney where they are involved in reabsorbing lactate. MCT1 is localized to the basolateral membrane of the renal proximal tubule together with CD147 [ 12 ], whereas MCT2 is found in the basolateral membrane of cells in the thick ascending limb of the loop of Henle [ 13 ]. The characterization of further members of the SLC16 family revealed that transport by MCTs is not limited to monocarboxylates. MCT8 transports thyroid hormone [ 14 ] and mutations of MCT8 associate with elevated levels of triiodothyronine (T3) and psychomotor retardation [ 15 ]. MCT10 is an aromatic amino acid transporter, also known as TAT1 (T-type amino acid transporter 1). Both transporters mediate transport in a proton (and sodium) independent manner [ 16 ], unlike the first 4 members. Recently MCT12, associated with juvenile cataract, was characterized as a creatine transporter [ 17 ], further widening the substrate spectrum of the MCT family. MCT12 local (...truncated)


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Thomas Knöpfel, Alexander Atanassoff, Nati Hernando, Jürg Biber, Carsten A. Wagner. Renal localization and regulation by dietary phosphate of the MCT14 orphan transporter, PLOS ONE, 2017, Volume 12, Issue 6, DOI: 10.1371/journal.pone.0177942