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PLoS One
2017 Jun 29;126:e0177942. doi: 10.1371/journal.pone.0177942.
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Renal localization and regulation by dietary phosphate of the MCT14 orphan transporter.
Knöpfel T
,
Atanassoff A
,
Hernando N
,
Biber J
,
Wagner CA
.
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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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28662032
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Fig 1. Renal adaptation to low (LPD) and high (HPD) dietary phosphate.Adaptation was confirmed by the expression of NaPi-IIa protein abundance in kidneys of mice fed 14 hours (A) and 5 days (B) with both diets. β-actin was used as a loading control. Renal mRNA expression of Cyp27b1 and MCT14 after either 14 hours (C and E) or 5 days (D and F) of LPD respectively HPD, n = 5–6 animals/group. Statistical differences were calculated with t-test: *p<0.05, **p<0.01 and ***p<0.001.
Fig 2. Validation of a newly generated MCT14 antibody.Renal homogenates were incubated with antibodies against MCT14 (A) and NaPi-IIa (B) in the presence and absence of the antigenic peptide as indicated. Lysates of Xenopus laevis oocytes injected with MCT14 cRNA and non-injected oocytes (n.i.) were incubated with the MCT14 antibody (C); renal homogenate was loaded in the last lane (+). Deglycosylated (+ PNGase) and native (- PNGase) renal homogenates were incubated with antibodies against MCT14 and NaPi-IIa (D). Immunofluorescence was performed on kidney cryosections in the presence and absence of the antigenic peptide (E). Immunofluorescence in oocytes expressing MCT14 and corresponding non-injected oocytes (F).
Fig 3. MCT14 renal localization.Consecutive sections showing MCT14 and NaPi-IIa localization (A). Cortical (B) and outer medullary (C) staining patterns of MCT14 and NKCC2 on consecutive sections. Costainings performed with MCT14 and uromodulin (D) or NCC (E) on renal sections. MCT14 is shown in red, NaPi-IIa, NKCC2, uromodulin and NCC are represented in green and blue indicates nuclear fluorescence (DAPI).
Fig 4. Regulation of MCT14 protein abundance by dietary phosphate.Western blotting with MCT14 antibody was performed on renal homogenates from animals fed 14 hours (A) and 5 days (B) with either low (LPD) or high (HPD) phosphate. Expression levels were normalized to corresponding β-actin levels. MCT14 protein abundance was significantly increased in animals fed a HPD compared to LPD as indicated in the corresponding densitometric analysis. Statistical differences were calculated with t-test: *p<0.05 and ***p<0.001. Immunofluorescence staining against MCT14 was performed in kidneys of mice fed HPD or LPD for 5 days (C).
Fig 5. Uptake in X. laevis oocytes.Lactate transport was assessed in Xenopus laevis oocytes injected with cRNA of MCT14 and CD147, in oocytes injected with MCT14 or CD147 alone and non-injected oocytes (NI) (A). Oocytes expressing MCT12 and CD147, MCT14, MCT14 and CD147 and non-expressing oocytes (N.I.) were used to perform creatine uptake (B). Transport of the indicated amino acids into oocytes expressing MCT14 is given in relation of uptakes into non-injected oocytes (NI) (C). Slc16a14 mRNA was detected in Xenopus laevis kidney but not oocytes (D). Each experiment was performed with at least n = 7–10 oocytes.
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