基于QPRT-NAD+-SIRT3-线粒体动力学通路探讨益气活血化浊法干预CKD肾小管间质纤维化的作用机制

我国慢性肾脏病（CKD）患病率为10.8%且呈增长趋势。肾小管间质纤维化与CKD进展及肾脏预后密切相关。前期研究表明以健脾益肾方为代表的益气活血化浊法可通过调节线粒体动力学延缓CKD进展及纤维化。然而该治法调控线粒体动力学的机制尚不清楚。烟酰胺腺嘌呤二核苷酸（NAD+）依赖的SIRT3是线粒体动力学调控的新靶点。我们预实验发现肾脏喹啉酸磷酸核糖转移酶（QPRT）-NAD+-SIRT3轴在CKD模型中显著下调。我们假设益气活血化浊法通过QPRT-NAD+-SIRT3调控线粒体动力学延缓CKD肾小管间质纤维化进展。本项目拟通过体内外实验从QPRT-NAD+-SIRT3-线粒体动力学通路研究益气活血化浊法延缓CKD肾小管间质纤维化进展的机制；并基于临床实践模式探讨益气活血化浊法联合RAS抑制剂对该通路的协同调节作用及靶点，为CKD中医益气活血化浊法现代科学内涵的揭示及其临床应用提供更多实验依据。

The prevalence of chronic kidney disease (CKD) in China is 10.8% and shows an increasing trend. Renal tubulointerstitial fibrosis is closely related to CKD progression and renal outcome. Our previous studies have shown that Yiqi Huoxue Huazhuo Treatment Method, represented by Jian-Pi-Yi-Shen Formula, can delay the progression of CKD and fibrosis by regulating mitochondrial dynamics. However, the mechanism by which this treatment method regulates mitochondrial dynamics is unclear. Nicotinamide adenine dinucleotide (NAD+)-dependent SIRT3 is a novel target of mitochondrial dynamics regulation. Our preliminary experiments revealed that the renal quinolinate phosphoribosyltransferase (QPRT)-NAD+-SIRT3 axis was significantly down-regulated in the CKD rat model. We hypothesized that Yiqi Huoxue Huazhuo Treatment Method can delay the progression of CKD tubulointerstitial fibrosis by regulating mitochondrial dynamics by QPRT-NAD+-SIRT3. This project intends to investigate the mechanism of Yiqi Huoxue Huazhuo Treatment Method for delaying the progression of CKD tubulointerstitial fibrosis by QPRT-NAD+-SIRT3-mitochondrial dynamics pathway in vitro and in vivo experiments; and to explore the synergistic regulation effects and targets of the combination of Yiqi Huoxue Huazhuo Treatment Method and renin-angiotensin system (RAS) inhibitors based on clinical practice mode. This project will provide more experimental evidence for the revealing of the modern scientific connotation of CKD TCM Yiqi Huoxue Huazhuo Treatment Method and its clinical application.