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Inhibitory role of microRNA-484 in kidney stone formation by repressing calcium oxalate crystallization via a VDR/FoxO1 regulator axis

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Abstract

Kidney stones are regarded as common malignant diseases in the developed world. As a result, significant research examining their formation is ongoing, with microRNAs (miRs) recently being linked with kidney stone formation. Here, we aim to define the potential role of miR-484 in regulating renal tubular epithelial cell (RTEC) viability and the attachment of calcium oxalate (CaOx) crystals to RTECs via vitamin D receptor (VDR)/forkhead box protein O1 (FoxO1) axis. The pathological condition of CaOx crystallization was induced and examined in Sprague–Dawley rats, while RTECs were isolated and cultured in vitro. Loss- and gain-function assays were performed to study the effects that miR-484, VDR, and FoxO1 on RTEC functions and CaOx crystallization in vitro and on kidney stone formation in vivo. The interaction between miR-484 and VDR was confirmed by dual-luciferase reporter gene assays. Downregulation of miR-484 and FoxO1 as well as overexpression of VDR were identified in kidney stone modelled rats. VDR was confirmed as a target gene of miR-484, while knockdown of VDR upregulated the FoxO1 expression. miR-484 overexpression or VDR suppression reduced RTEC cytotoxicity and crystal attachment to RTECs in vitro and reduced the CaOx crystallization in vivo. Taken together, these findings suggest that miR-484 overexpression may be a potential inhibitor of RTEC proliferation and CaOx crystallization through a VDR/FoxO1 regulatory axis, providing a novel therapeutic target for the treatment of kidney stone.

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Acknowledgements

We would like to acknowledge the reviewers for their helpful comments on this study.

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Authors and Affiliations

  1. Department of Urology, China–Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, Jilin Province, People’s Republic of China

    Li Fan, Hai Li & Wei Huo

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  1. Li Fan
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  2. Hai Li
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  3. Wei Huo
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Contributions

LF and WH: designed the study. LF and HL: collated the data, carried out data analyses and produced the initial draft of the manuscript. HL and WH: contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Wei Huo.

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Fan, L., Li, H. & Huo, W. Inhibitory role of microRNA-484 in kidney stone formation by repressing calcium oxalate crystallization via a VDR/FoxO1 regulator axis. Urolithiasis 50, 665–678 (2022). https://doi.org/10.1007/s00240-022-01359-6

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