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)