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Acute kidney injury (AKI) is a common clinical disease that can cause serious harm to the kidneys, but it has no effective treatment till now. The modulation of autophagy pathway regulation is considered a potentially effective therapeutic approach in AKI prevention and treatment. ZKSCAN3 has been shown to be an important transcription factor that negatively regulates autophagy activity in cancer tissues. In order to determine whether autophagy could be activated by knocking out ZKSCAN3 to exert the renal protective effect of autophagy, we constructed AKI models with Zkscan3 knockout (KO) mice and detected renal pathological changes and renal function changes as well as autophagy-related indicators. We found that Zkscan3 KO had no significant effect on kidney development. Besides, no significant changes in autophagy activity were observed under normal physiological or AKI conditions. In non-tumor tissues, ZKSCAN3 did not mediate transcriptional regulation of autophagy-related genes. These findings suggest that because ZKSCAN3 may not function in the transcriptional regulation of autophagy-related genes in non-tumor tissues, it may not be used as a therapeutic target for AKI.

BackgroundKidney stone formers with family history have a high rate of stone recurrence after kidney stone removal surgery and there is no effective medication available for treatment. It has been shown that hydroxycitric acid (HCA)-the major component of Garcinia cambogia extract, induces dissolution of the calcium oxalate crystal in vitro, suggesting that clinical-grade Garcinia cambogia has the potential to treat calcium oxalate kidney stone. In this study, we used the Drosophila genetic and non-genetic nephrolithiasis model to evaluate the effect of Garcinia cambogia and HCA on the prevention and removal of calcium oxalate stones in vivo. Methods: WT flies were reared in fly food with different concentrations of GCE for one week．The effect of GCE on preventing the formation of calcium oxalate stone was examined. WT and v-ATPase gene knockdown flies were reared in fly food containing 0.3% NaOx for one week, then fed different concentrations of GCE for one week．The effect of GCE on the removal of calcium oxalate stone was examined. Findings: Garcinia cambogia extract efficiently removes calcium oxalate kidney stones from Malpighian tubules in both genetic and non-genetic Drosophila models of nephrolithiasis in vivo. HCA directly dissolves calcium oxalate stones in Drosophila Malpighian tubules ex vivo. Interpretation: Clinical-grade Garcinia cambogia extract removes calcium oxalate kidney stones from Drosophila Malpighian tubules via directly dissolving calcium oxalate stones by HCA. Our study strongly suggests that clinical-grade Garcinia cambogia extract could be used to treat patients with nephrolithiasis in the future. Funding Statement: F.J.Z. was supported by grants from National Key Research Plan (2017YFA0104602) and F.F.H was supported by the National Key Technology Support Program of China (2013BAI09B06 and 2015BAI2B07), the State Key Program of National Natural Science Foundation of China (81430016), the Major International (Regional) Joint Research Project of National Natural Science Foundation of China (81620108003), the Major Scientific and Technological Planning Project of Guangzhou (15020010), and the Guangzhou Clinical Research Center for Chronic Kidney Disease Program (7415695988305). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The authors state: "Not applicable"

Kidney stone formers with family history have a high rate of stone recurrence after kidney stone removal surgery and there is no effective medication available for treatment. Here, we show that Garcinia cambogia extract (GCE) efficiently removes calcium oxalate kidney stones from Malpighian tubules in both genetic and non-genetic Drosophila models of nephrolithiasis, and hydroxycitrate -a major component of GCE, directly dissolves calcium oxalate stones in Drosophila Malpighian tubules ex vivo. Our study discovers a potential novel therapeutic strategy for the clinical treatment of nephrolithiasis and suggests that clinical-grade Garcinia cambogia extract could be used to treat patients with nephrolithiasis in the future.