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

研究成果: 雜誌貢獻文章同行評審

8 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
文章編號8085
期刊Scientific Reports
8
發行號1
DOIs
出版狀態已發佈 - 十二月 1 2018

ASJC Scopus subject areas

  • 多學科

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