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Abstract: PO0432

The Susceptibility Mechanism of AKI in Cirrhosis Through Regulation of miR-599 Mediated by SIRT1 rs4746720 Polymorphism

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Chen, Yixin, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
  • Zhou, Fangfang, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
  • Xu, Youjun, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
  • Lu, Yi, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
  • Luo, Qun, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
Background

Previous study has confirmed that SIRT1/PGC-1α signaling pathway might be involved in the pathogenesis of acute kidney injury (AKI) in cirrhosis. This study aimed to analyze the association between SIRT1 single nucleotide polymorphism (SNP) and the risk of AKI in cirrhosis in a Chinese Han population, and to further explore the molecular mechanism of SIRT1 SNP in vitro.

Methods

A total of 29 patients in AKI group and 87 patients in control group were selected from a Chinese Han population. Genotypes of SIRT1 rs4746720 and rs2273773 were detected by SnaPshot technology. Bioinformatics softwares predicted that miR-599 might bind to the rs4746720 loci within SIRT1 3'UTR. The dual luciferase reporter vectors pmir-GLO-SIRT1-3'UTR-T/C were constructed and respectively co-transfected with miR-599 mimic or NC into HK-2 cells. The overexpression recombinant plasmids pcDNA3.1-SIRT1 -T/C were further constructed and respectively co-transfected with miR-599 mimic, miR-599 inhibitor or NC into HK-2 cells, and the expression of miR-599 and SIRT1/PGC-1α/NRF1/TFAM were detected by qRT-PCR and Western blot.

Results

There was no significant association between SIRT1 SNP and the risk of AKI in cirrhosis (P>0.05). But stratified analysis based on risk factors showed that in the subgroup of hepatic encephalopathy, SIRT1 rs4746720 polymorphism was significantly associated with the risk of AKI in cirrhosis (OR=6.00, 95%CI: 1.22-29.48, P=0.027). Analysis of liver and kidney function showed that Scr and BUN of TT genotype of SIRT1 rs4746720 was significantly higher than that of CC+CT genotype in the AKI group, and eGFR was significantly lower than that of CC+CT genotype (P<0.05). Dual luciferase reporter vectors showed that rs4746720 T allele of SIRT1 could increase the binding of miR-599, which resulted in significantly reduced luciferase activity (P<0.001). Overexpression recombinant plasmids showed that rs4746720 T allele of SIRT1 could mediate the binding of miR-599, which resulted in significantly reduced expression of SIRT1 and its downstream pathway (P<0.05).

Conclusion

The rs4746720 polymorphism in SIRT1 3'UTR may be associated with the risk of AKI in patients with cirrhosis. The rs4746720 T allele of SIRT1 may mediate the binding of miR-599, affect the expression of SIRT1 and its downstream pathway.