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Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels

Acute or chronic kidney disease can cause micronutrient deficiency. Patients with end-stage renal disease, kidney transplantation or on dialysis have reduced circulating levels of folate, an essential B vitamin. However, the molecular mechanism is not well understood. Reabsorption of folate in renal...

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Autores principales: Yang, Cheng, Wijerathne, Charith U. B., Tu, Guo-wei, Woo, Connie W. H., Siow, Yaw L., Madduma Hewage, Susara, Au-Yeung, Kathy K. W., Zhu, Tongyu, O, Karmin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213029/
https://www.ncbi.nlm.nih.gov/pubmed/34149715
http://dx.doi.org/10.3389/fimmu.2021.678914
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author Yang, Cheng
Wijerathne, Charith U. B.
Tu, Guo-wei
Woo, Connie W. H.
Siow, Yaw L.
Madduma Hewage, Susara
Au-Yeung, Kathy K. W.
Zhu, Tongyu
O, Karmin
author_facet Yang, Cheng
Wijerathne, Charith U. B.
Tu, Guo-wei
Woo, Connie W. H.
Siow, Yaw L.
Madduma Hewage, Susara
Au-Yeung, Kathy K. W.
Zhu, Tongyu
O, Karmin
author_sort Yang, Cheng
collection PubMed
description Acute or chronic kidney disease can cause micronutrient deficiency. Patients with end-stage renal disease, kidney transplantation or on dialysis have reduced circulating levels of folate, an essential B vitamin. However, the molecular mechanism is not well understood. Reabsorption of folate in renal proximal tubules through folate transporters is an important process to prevent urinary loss of folate. The present study investigated the impact of acute kidney injury (AKI) on folate transporter expression and the underlying mechanism. AKI was induced in Sprague-Dawley rats that were subjected to kidney ischemia (45 min)-reperfusion (24 h). Both male and female rats displayed kidney injury and low plasma folate levels compared with sham-operated rats. The plasma folate levels were inversely correlated to plasma creatinine levels. There was a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) and IL-6 mRNA expression in the kidneys of rats with ischemia-reperfusion, indicating kidney injury and increased inflammatory cytokine expression. Ischemia-reperfusion decreased mRNA and protein expression of folate transporters including folate receptor 1 (FOLR1) and reduced folate carrier (RFC); and inhibited transcription factor Sp1/DNA binding activity in the kidneys. Simulated ischemia-reperfusion through hypoxia-reoxygenation or Sp1 siRNA transfection in human proximal tubular cells inhibited folate transporter expression and reduced intracellular folate levels. These results suggest that ischemia-reperfusion injury downregulates renal folate transporter expression and decreases folate uptake by tubular cells, which may contribute to low folate status in AKI. In conclusion, ischemia-reperfusion injury can downregulate Sp1 mediated-folate transporter expression in tubular cells, which may reduce folate reabsorption and lead to low folate status.
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spelling pubmed-82130292021-06-19 Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels Yang, Cheng Wijerathne, Charith U. B. Tu, Guo-wei Woo, Connie W. H. Siow, Yaw L. Madduma Hewage, Susara Au-Yeung, Kathy K. W. Zhu, Tongyu O, Karmin Front Immunol Immunology Acute or chronic kidney disease can cause micronutrient deficiency. Patients with end-stage renal disease, kidney transplantation or on dialysis have reduced circulating levels of folate, an essential B vitamin. However, the molecular mechanism is not well understood. Reabsorption of folate in renal proximal tubules through folate transporters is an important process to prevent urinary loss of folate. The present study investigated the impact of acute kidney injury (AKI) on folate transporter expression and the underlying mechanism. AKI was induced in Sprague-Dawley rats that were subjected to kidney ischemia (45 min)-reperfusion (24 h). Both male and female rats displayed kidney injury and low plasma folate levels compared with sham-operated rats. The plasma folate levels were inversely correlated to plasma creatinine levels. There was a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) and IL-6 mRNA expression in the kidneys of rats with ischemia-reperfusion, indicating kidney injury and increased inflammatory cytokine expression. Ischemia-reperfusion decreased mRNA and protein expression of folate transporters including folate receptor 1 (FOLR1) and reduced folate carrier (RFC); and inhibited transcription factor Sp1/DNA binding activity in the kidneys. Simulated ischemia-reperfusion through hypoxia-reoxygenation or Sp1 siRNA transfection in human proximal tubular cells inhibited folate transporter expression and reduced intracellular folate levels. These results suggest that ischemia-reperfusion injury downregulates renal folate transporter expression and decreases folate uptake by tubular cells, which may contribute to low folate status in AKI. In conclusion, ischemia-reperfusion injury can downregulate Sp1 mediated-folate transporter expression in tubular cells, which may reduce folate reabsorption and lead to low folate status. Frontiers Media S.A. 2021-06-04 /pmc/articles/PMC8213029/ /pubmed/34149715 http://dx.doi.org/10.3389/fimmu.2021.678914 Text en Copyright © 2021 Yang, Wijerathne, Tu, Woo, Siow, Madduma Hewage, Au-Yeung, Zhu and O https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yang, Cheng
Wijerathne, Charith U. B.
Tu, Guo-wei
Woo, Connie W. H.
Siow, Yaw L.
Madduma Hewage, Susara
Au-Yeung, Kathy K. W.
Zhu, Tongyu
O, Karmin
Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels
title Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels
title_full Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels
title_fullStr Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels
title_full_unstemmed Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels
title_short Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels
title_sort ischemia-reperfusion injury reduces kidney folate transporter expression and plasma folate levels
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213029/
https://www.ncbi.nlm.nih.gov/pubmed/34149715
http://dx.doi.org/10.3389/fimmu.2021.678914
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