A novel SNP in the 5' regulatory region of organic anion transporter 1 is associated with chronic kidney disease

Chiao Yin Sun, Mai Szu Wu, Chin Chan Lee, Shu Hong Chen, Kang Chieh Lo, Yau Hung Chen

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Abstract

We aimed to analyze the associations of single nucleotide polymorphisms (SNP) in the 5′ regulatory region of the human organic anion transporter 1 (OAT1) gene with chronic kidney disease (CKD). A case-control study including age-and sex-matched groups of normal subjects and patients with CKD (n = 162 each) was designed. Direct sequencing of the 5′ regulatory region (+88 to-1196 region) showed that patients with CKD had a higher frequency of the-475 SNP (T > T/G) than normal subjects (14/162 vs. 2/162). The luciferase activity assay results indicated that the-475G SNP had a higher promoter efficiency than the-475T SNP. Chromatin immunoprecipitation (ChIP) and LC/MS/MS analyses showed that the-475G SNP up-regulated 26 proteins and down-regulated 74 proteins. The Southwestern blot assay results revealed that the-475G SNP decreased the binding of Hepatoma-derived growth factor (HDGF), a transcription repressor, compared to the-475T SNP. Overexpression of HDGF significantly down-regulated OAT1 in renal tubular cells. Moreover, a zebrafish animal model showed that HDGF-knockdown zebrafish embryos had higher rates of kidney malformation than wild-Type controls [18/78 (23.1%) vs. 1/30 (3.3%)]. In conclusion, our results suggest that an OAT1 SNP might be clinically associated with CKD. Renal tubular cells with the-475 SNP had increased OAT1 expression, which resulted in increased transportation of organic anion toxins into cells. Cellular accumulation of organic anion toxins caused cytotoxicity and resulted in CKD.

Original languageEnglish
Article number8085
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Organic Anion Transporters
Nucleic Acid Regulatory Sequences
Chronic Renal Insufficiency
Single Nucleotide Polymorphism
Zebrafish
Kidney
Anions
Southwestern Blotting
Chromatin Immunoprecipitation
Luciferases
Case-Control Studies
Proteins
Research Design
Embryonic Structures
Animal Models

ASJC Scopus subject areas

  • General

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A novel SNP in the 5' regulatory region of organic anion transporter 1 is associated with chronic kidney disease. / Sun, Chiao Yin; Wu, Mai Szu; Lee, Chin Chan; Chen, Shu Hong; Lo, Kang Chieh; Chen, Yau Hung.

In: Scientific Reports, Vol. 8, No. 1, 8085, 01.12.2018.

Research output: Contribution to journalArticle

Sun, Chiao Yin ; Wu, Mai Szu ; Lee, Chin Chan ; Chen, Shu Hong ; Lo, Kang Chieh ; Chen, Yau Hung. / A novel SNP in the 5' regulatory region of organic anion transporter 1 is associated with chronic kidney disease. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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abstract = "We aimed to analyze the associations of single nucleotide polymorphisms (SNP) in the 5′ regulatory region of the human organic anion transporter 1 (OAT1) gene with chronic kidney disease (CKD). A case-control study including age-and sex-matched groups of normal subjects and patients with CKD (n = 162 each) was designed. Direct sequencing of the 5′ regulatory region (+88 to-1196 region) showed that patients with CKD had a higher frequency of the-475 SNP (T > T/G) than normal subjects (14/162 vs. 2/162). The luciferase activity assay results indicated that the-475G SNP had a higher promoter efficiency than the-475T SNP. Chromatin immunoprecipitation (ChIP) and LC/MS/MS analyses showed that the-475G SNP up-regulated 26 proteins and down-regulated 74 proteins. The Southwestern blot assay results revealed that the-475G SNP decreased the binding of Hepatoma-derived growth factor (HDGF), a transcription repressor, compared to the-475T SNP. Overexpression of HDGF significantly down-regulated OAT1 in renal tubular cells. Moreover, a zebrafish animal model showed that HDGF-knockdown zebrafish embryos had higher rates of kidney malformation than wild-Type controls [18/78 (23.1{\%}) vs. 1/30 (3.3{\%})]. In conclusion, our results suggest that an OAT1 SNP might be clinically associated with CKD. Renal tubular cells with the-475 SNP had increased OAT1 expression, which resulted in increased transportation of organic anion toxins into cells. Cellular accumulation of organic anion toxins caused cytotoxicity and resulted in CKD.",
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