A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease.
A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease.
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果蝇模型确定了锌在肾脏疾病的矿化中的关键作用。
DOI：
10.1371/journal.pone.0124150
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Stoller ML
中科院分区：
文献类型：
--
作者：
Chi T;Kim MS;Lang S;Bose N;Kahn A;Flechner L;Blaschko SD;Zee T;Muteliefu G;Bond N;Kolipinski M;Fakra SC;Mandel N;Miller J;Ramanathan A;Killilea DW;Brückner K;Kapahi P;Stoller ML
异位钙化是包括肾结石和动脉粥样硬化在内的多种疾病的驱动力，但引发因素在很大程度上仍不清楚。鉴于它在看似不同的疾病过程中的重要性，确定异位钙化的基本主要因素可能具有广泛的翻译意义。在这里，我们通过抑制黄嘌呤脱氢酶来建立果蝇异位钙化的黑腹果蝇模型，黄嘌呤脱氢酶缺乏会导致人和狗的肾结石。微型X射线吸收近边缘光谱分析(μXANES)同步加速器分析显示，果蝇体内相当于肾结石的锌含量很高，在人类肾结石和兰德尔斑块(在人类肾脏中发现的早期钙化被认为是肾结石的前兆)中也观察到了这种情况。为了进一步测试锌在驱动矿化中的作用，我们抑制了ZNT家族中的锌转运蛋白基因，并观察到对果蝇结石形成的抑制。综上所述，遗传、饮食和药物干预降低锌证实了锌在驱动最终导致结石形成的异质成核过程中的关键作用。我们的发现为尿路结石和相关疾病的病因学开辟了一个新的视角，这可能导致新的预防和治疗方法的确定。
Ectopic calcification is a driving force for a variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors for ectopic calcification may have broad translational significance. Here we establish a Drosophila melanogaster model for ectopic calcification by inhibiting xanthine dehydrogenase whose deficiency leads to kidney stones in humans and dogs. Micro X-ray absorption near edge spectroscopy (μXANES) synchrotron analyses revealed high enrichment of zinc in the Drosophila equivalent of kidney stones, which was also observed in human kidney stones and Randall’s plaques (early calcifications seen in human kidneys thought to be the precursor for renal stones). To further test the role of zinc in driving mineralization, we inhibited zinc transporter genes in the ZnT family and observed suppression of Drosophila stone formation. Taken together, genetic, dietary, and pharmacologic interventions to lower zinc confirm a critical role for zinc in driving the process of heterogeneous nucleation that eventually leads to stone formation. Our findings open a novel perspective on the etiology of urinary stones and related diseases, which may lead to the identification of new preventive and therapeutic approaches.
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