肾脏Npt调节线粒体磷稳态和管球反馈参与药物相关范可尼综合征的机制研究

药物导致范可尼综合征是急慢性肾功能损害的重要原因，目前还缺乏系统的机制研究，难以预测其风险。本研究首先分析替诺福韦肾损伤队列遗传易感性，构建药物肾损伤模型；证实遗传和获得性近端小管钠磷转运子（Npt2a）异常导致范可尼和GFR降低；进而建立Npt2a不同突变背景的斑马鱼模型，证实线粒体内低磷是线粒体产能障碍，是导致肾小管主动转运障碍和范可尼综合征的关键；最后利用管球反馈（TGF）缺失A1AR和Npt2a基因敲除小鼠、球旁器致密斑（MD）-颗粒细胞共培养模型和入球动脉显微灌注技术，从体内、组织、细胞和分子水平首次证实：MD上Npt2a能感知高尿磷，激活TGF、抑制肾素分泌，收缩入球、扩张出球动脉导致GFR降低的新管球反馈机制。最终证实Npt2a对于保证线粒体供能近端小管，触发致密斑TGF，调节肾小球GFR的关键环节，为药物肾损伤危险分层和防治提供的新思路和潜在干预位点。

The renal Fanconi syndrome induced by antiviral therapy is an important reason of acute or chronic renal injury without intensive mechanism study. First, we would observe the genetic predisposition in a cohort study of patients with tenofovir-induced renal injury, then establish the renal Fanconi syndrome and GFR reduction with Na-P transporter (Npt2a) disorder in mice models. Secondly, the different Npt2a mutations are used to construct in zebrafish and mice model to confirm that low phosphate in mitochondria impairs the energy production and leading Fanconi syndrome. Finally, the tubulo-glomerular feedback (TGF)-deficient A1AR-Npt2a double knock out mice, vitro macular densa (MD)-JGC co-culture model and micro-perfusion of afferent arterioles, will be used to clarify a new molecular mechanism of TGF mediated by Npt2a in MD. The co-operation of TGF and decrease of renin secretion lead the GFR reduction. Thus, we conclude that Npt2a plays an essential role in guaranteeing the energy supply of proximal tubule from mitochondria, as well as triggering TGF of MD in GFR regulation. It is supposed to provide a new idea for early warning, prevention and therapy strategies in drug-induced renal injury.