Human MiR-4660 regulates the expression of alanine-glyoxylate aminotransferase and may be a biomarker for idiopathic oxalosis

BackgroundDysfunction of oxalate synthesis can cause calcium oxalate stone disease and inherited primary hyperoxaluria (PH) disorders. PH type I (PH1) is one of the most severe hyperoxaluria disorders, which results in urolithiasis, nephrocalcinosis, and end-stage renal disease. Here, we sought to determine the role of microRNAs in regulating AGXT to contribute to the pathogenesis of mutation-negative idiopathic oxalosis.MethodsWe conducted bioinformatics to search for microRNAs binding to AGXT, and examined the expression of the highest hit (miR-4660) in serum samples of patients with oxalosis, liver tissue samples, and determined the correlation and regulation between the microRNA and AGXT in vitro.ResultsMiR-4660 expression was downregulated in patients with oxalosis compared with healthy controls (84.03 copies/mu L vs 33.02 copies/mu L, P<0.0001). Moreover, miR-4660 epigenetically decreased the expression of AGT in human liver tissues (Rho=-0543, P=0.037). Overexpression of miR-4660 in HepG2 and L02 cell lines led to dysregulation of AGXT at both the mRNA (by 71% and 81%, respectively; P<0.001) and protein (by 49% and 42%, respectively; P<0.0001) levels. We confirmed the direct target site of miR-4660 binding to the 3UTR of AGXT by a luciferase assay.ConclusionMiR-4660 is probably a new biomarker for mutation-negative idiopathic oxalosis by regulating the post-transcription of AGXT, providing a potential treatment target of mutation-negative idiopathic oxalosis.