Abstract
Background
Dysfunction 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.
Methods
We 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.
Results
MiR-4660 expression was downregulated in patients with oxalosis compared with healthy controls (84.03 copies/µL vs 33.02 copies/µL, 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 3′UTR of AGXT by a luciferase assay.
Conclusion
MiR-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.
Similar content being viewed by others
References
Holmes RP, Assimos DG. Glyoxylate synthesis, and its modulation and influence on oxalate synthesis. J Urol. 1998;160:1617–24.
Salido E, Pey AL, Rodriguez R, Lorenzo V. Primary hyperoxalurias: disorders of glyoxylate detoxification. Biochim Biophys Acta. 2012;1822:1453–64.
Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 2012;8:467–75.
Hoppe B, Dittlich K, Fehrenbach H, Plum G, Beck BB. Reduction of plasma oxalate levels by oral application of Oxalobacter formigenes in 2 patients with infantile oxalosis. Am J Kidney Dis. 2011;58:453–5.
M’Dimegh S, Aquaviva-Bourdain C, Omezzine A, M’Barek I, Souche G, Zellama D, et al. A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype-phenotype correlation. J Genet. 2016;95:659–66.
Danpure CJ. Variable peroxisomal and mitochondrial targeting of alanine: glyoxylate aminotransferase in mammalian evolution and disease. Bioessays. 1997;19:317–26.
Danpure CJ, Purdue PE, Fryer P, Griffiths S, Allsop J, Lumb MJ, et al. Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet. 1993;53:417–32.
Cellini B, Montioli R, Voltattorni CB. Human liver peroxisomal alanine:glyoxylate aminotransferase: characterization of the two allelic forms and their pathogenic variants. Biochim Biophys Acta. 2011;1814:1577–84.
Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci USA. 2003;100:7277–82.
Du DF, Li QQ, Chen C, Shi SM, Zhao YY, Jiang JP, et al. Updated genetic testing of primary hyperoxaluria type 1 in a Chinese population: results from a single center study and a systematic review. Curr Med Sci. 2018;38:749–57.
Hoppe B. Evidence of true genotype-phenotype correlation in primary hyperoxaluria type 1. Kidney Int. 2010;77:383–5.
Lynn FC. Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol Metab. 2009;20:452–9.
Rivera-Barahona A, Perez B, Richard E, Desviat LR. Role of miRNAs in human disease and inborn errors of metabolism. J Inherit Metab Dis. 2017;40:471–80.
Ferracin M, Negrini M. Quantification of circulating microRNAs by droplet digital PCR. Methods Mol Biol. 2018;1768:445–57.
Zhao Y, Huang Y, Li W, Wang Z, Zhan S, Zhou M, et al. Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p. Biochim Biophys Acta. 2015;1852:2024–34.
Meseguer S, Martinez-Zamora A, Garcia-Arumi E, Andreu AL, Armengod ME. The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet. 2015;24:167–84.
Martino F, Carlomosti F, Avitabile D, Persico L, Picozza M, Barilla F, et al. Circulating miR-33a and miR-33b are up-regulated in familial hypercholesterolaemia in paediatric age. Clin Sci. 2015;129:963–72.
Li Y, Peng T, Wang X, Duan R, Gao H, Guan W, et al. A primary study on down-regulated miR-9-1 and its biological significances in methylmalonic acidemia. J Mol Neurosci. 2014;53:280–6.
Liu Z, Jiang H, Yang J, Wang T, Ding Y, Liu J, et al. Analysis of altered microRNA expression profiles in the kidney tissues of ethylene glycol-induced hyperoxaluric rats. Mol Med Rep. 2016;14:4650–8.
ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
Choucair N, Rajab M, Megarbane A. Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation. Am J Med Genet A. 2017. https://doi.org/10.1002/ajmg.a.38271
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Nos. 91439109, 81700300, 81870176 and 91439109) and the Program for New Century Excellent Talents at the University of China (NCET-11-0181).
Author information
Authors and Affiliations
Contributions
XT and DD designed the study. YZ, QL, XY and SS performed the experiments and statistical analysis. YY, ZD, YM, ZZ, XW and JJ collected the samples and took part in finishing the experiments.
Corresponding author
Ethics declarations
Conflict of interest
All authors do not have any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within 3 years.
Human and animal rights
This study was approved by the appropriate local institutional review boards on human subject research at the Tongji Hospital of Huazhong University of Science and Technology (IRB ID: TJ-C20160114) and conformed to the guidelines set forth by the Declaration of Helsinki.
Informed consent
Written informed consent was obtained from all participants.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Tu, X., Zhao, Y., Li, Q. et al. Human MiR-4660 regulates the expression of alanine–glyoxylate aminotransferase and may be a biomarker for idiopathic oxalosis. Clin Exp Nephrol 23, 890–897 (2019). https://doi.org/10.1007/s10157-019-01723-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10157-019-01723-8