MicroRNA-599-Regulated Susceptibility to Acute Kidney Injury in Patients with Cirrhosis is Mediated by the Sirtuin 1 (SIRT1) rs4746720 Single Nucleotide Polymorphism

Objective: The aim of this case-control study was to analyze the association between sirtuin 1 (SIRT1) single nucleotide polymorphism (SNP) and the risk of acute kidney injury (AKI) in Han Chinese patients with cirrhosis and to explore its potential mechanism.

Methods: Twenty-nine AKI patients with cirrhosis (AKI group) and 87 non-AKI patients with cirrhosis (control group) were recruited from a Han Chinese population. SNaPshot sequencing technology was used for the detection of SNPs. Dual luciferase reporter vectors were constructed and co-transfected into HK-2 human proximal tubular epithelial cells. SIRT1-overexpressing recombinant plasmids were constructed and co-transfected into HK-2 cells. The expression of microRNA-599 (miR-599) and SIRT1/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) was detected by the quantitative polymerase chain reaction, and the expression of the corresponding proteins was detected by Western blotting.

Results: There were no statistically significant between-group differences in the genotype and allele frequencies of SIRT1 rs4746720. In the subgroup of patients with hepatic encephalopathy, the SIRT1 rs4746720 SNP was significantly associated with the development of AKI, and the risk of AKI in patients with the T allele was six times higher than in those with the C allele. The results of the in vitro experiments demonstrated that the T allele of SIRT1 rs4746720 increased the binding of miR-599 to the rs4746720 locus within the 3'-UTR of SIRT1 (p < 0.001). The results of the SIRT1-overexpressing recombinant plasmid experiments confirmed that the T allele of SIRT1 rs4746720 mediated the binding of miR-599, leading to decreased SIRT1 and PGC-1α, NRF1, and TFAM (p < 0.05).

Conclusions: The SIRT1 rs4746720 SNP might be linked with AKI in cirrhotic patients, and the T allele increased the risk of AKI in those with hepatic encephalopathy. The rs4746720 SNP in the SIRT1 3'-UTR is linked to the development of AKI in cirrhotic patients with hepatic encephalopathy, potentially by mediating the binding of miR-599.