Arbutin as a Therapeutic Agent Against Calcium Oxalate-Induced Crystal Deposition and Kidney Injury

Kidney stone is one of the most common urologic diseases worldwide. In general, about 80% of kidney stones are composed of calcium oxalate (CaOx) and calcium phosphate. Activation of oxidative stress has been commonly recognized as a key target for CaOx nephrolithiasis. In this respect, it is important to identify novel and effective antioxidant agents for CaOx nephrolithiasis therapy. Arbutin, a glycosylated compound of hydroquinone, plays a protective role in many organs such as neuron, heart and liver by mitigating oxidative stress. Nevertheless, it remains unclear whether, and if so how, arbutin improvs CaOx-induced crystal deposition and kidney injury. Here, a mouse model of CaOx nephrolithiasis was established by feeding high-oxalate diet removed calcium. TMT proteomics was used to discover possible targets for arbutin. We observed that arbutin reduced CaOx crystal deposition and increased cell viability in HK-2 cells. Proteomics data revealed that the expression of Nrf2 downstream effectors were upregulated in CaOx crystal and arbutin co-treated HK-2 cells, compared with CaOx crystal-only treated HK-2 cells. Molecular docking predicted the binding between arbutin and Nrf2-Keap1 complex was stable. CaOx crystal-induced activation of oxidative stress also could be alleviated by arbutin in HK-2 cells and mouse kidney tissue. Furthermore, mouse model of CaOx nephrolithiasis received arbutin improved CaOx -induced crystal deposition and kidney injury. Administration of arbutin enhanced Nrf2 and p-Nrf2 expression in CaOx crystal treated HK-2 cells and mouse kidney tissue. Further, suppression of Nrf2 by its inhibitor ML385 not only aggravated CaOx -induced crystal deposition and kidney injury but also abolished the therapeutic effect of arbutin on CaOx nephrolithiasis. Finally, ML385 and Nrf2-siRNA abrogated the protective effect of arbutin against CaOx crystal-induced oxidative stress. In summary, arbutin improves CaOx-induced crystal deposition and kidney injury via activating Nrf2, which have important clinical implications in the treatment of CaOx nephrolithiasis.