HIF-1α调节糖脂代谢介导肾间质纤维化的机制研究

Renal interstitial fibrosis contributes to the development of end stage renal failure. Dysregulation of glucose and fatty acid metabolism is one of the major mechanisms underlying renal fibrosis. Hypoxia inducible factor-1α (HIF-1α) plays key role in mediating renal fibrosis. However, the mechanism remains unclear. Here, the aim of this study is to investigate whether HIF-1α promotes the pathogenesis of renal interstitial fibrosis through regulation of glucose and fatty acid metabolism. The changes of HIF-1α, glucose and fatty acid metabolism will be evaluated in fibrosis kidneys. Tubular cell specific Hif-1α knockout mice and HIF-1α stabilizer will be applied to examine the regulation of HIF-1α on glucose and fatty acid metabolism as well as the development of fibrosis. Moreover, the effects of inhibiting glycolysis, interfering fatty acid anabolism and/or facilitating fatty acid oxidation will be determined. Furthermore, metabolomics analysis will be used to detect whether metabolites lead to the continuous stabilization of HIF-1α. In this study, we will explore whether HIF-1α is the key regulator of glucose and fatty acid metabolism in the pathogenesis of renal interstitial fibrosis. This will help understand the regulation mechanism of glucose and fatty acid metabolism and design novel therapeutic methods for chronic kidney disease.

肾间质纤维化导致终末期肾衰竭的过程中，糖脂代谢异常是其主要机制之一。缺氧诱导因子-1α(HIF-1α)在肾间质纤维化中发挥关键作用。本项目旨在研究HIF-1α是否通过调控糖脂代谢介导肾间质纤维化的作用及机制。观察肾纤维化组织中HIF-1α表达与糖脂代谢变化之间的差异；肾小管上皮细胞特异性Hif-1α缺失小鼠的糖脂代谢变化、HIF-1α稳定剂能否改变糖脂代谢以及与肾间质纤维化发生发展的关系。明确抑制糖酵解、干扰脂质合成和促进脂肪酸氧化对HIF-1α稳定剂诱导的肾间质纤维化的影响；同时借助代谢组学技术，观察代谢中间产物是否调控HIF-1α的持续稳定。本项目着重探讨HIF-1α是否是肾间质纤维化过程中调节糖脂代谢的关键分子，这将有助于人们认识肾间质纤维化中糖脂代谢的调控机制，可能为未来设计新的治疗方案提供理论依据。

肾间质纤维化导致终末期肾衰竭的过程中，糖脂代谢异常是其主要机制之一。缺氧诱导因子-1α（HIF-1α）在肾间质纤维化中发挥关键作用。本项目旨在研究HIF-1α是否通过调控糖脂代谢介导肾间质纤维化的作用及机制。我们发现HIF-1α在慢性肾脏病患者及动物模型的肾小管中稳定表达，伴随脂肪酸氧化向有氧糖酵解的代谢重编程，药物或基因干预HIF-1α能够影响糖脂代谢，进而调控肾纤维化的发生发展。HIF-1α调节的糖酵解关键酶丙酮酸激酶2（PKM2）介导间质成纤维细胞与肾小管上皮细胞的相互作用，减轻后者的损伤后死亡；PKM2还能缓解损伤造成的足细胞去分化和增殖，减轻肾小球硬化。有氧糖酵解产物乳酸诱导肾小管上皮细胞表型转化和间质成纤维细胞活化增殖。此外，脂肪酸氧化关键酶肉碱棕榈酰基转移酶1α（CPT1α）调控线粒体呼吸促进肾小管上皮细胞损伤后修复，线粒体代谢关键酶丙酮酸脱氢酶（PDHE1α）的乙酰化修饰调控肾纤维化，三羧酸循环代谢中间产物衣康酸酯调节炎症体活化，减轻肾间质纤维化。研究证实肾间质纤维化中调控HIF-1α稳定表达的机制包括Tsc1/mTOR/S6信号及UCP2/线粒体/缺氧途径。在此基础上，发现CPT1α、代谢物、IL-18等潜在的新型生物标志物，可能用于临床早期诊断。本项目成果发表期刊论文13篇，编写学术专著3部，荣获华夏医学科技奖1项，申请专利4项，2项已授权，国内学术会议特邀报告7场，培养博士研究生5名，硕士研究生6名。有助于人们认识肾间质纤维化中糖脂代谢的调控机制，为未来设计新的治疗方案奠定理论依据。