肾脏内皮细胞A-FABP在肥胖相关性肾病形成中的作用和机制研究

Adipocyte fatty acid binding protein (A-FABP) has a critical role in obesity-induced disorders, but the role of A-FABP in the development of obesity-associated nephropathy is unclear. In our preliminary data, A-FABP level was significantly increased in kidneys from high fat diet-fed mice, and positively correlated with the levels of renal pathophysiological markers. Endothelial cells were main sources of A-FABP, which mediating fatty acid uptake. Furthermore, there was existed A-FABP/CD36 complex in renal tissues. Therefore, our current project proposes renal endothelial A-FABP regulates fatty acid uptake, and stimulates lipid deposits to damage renal structure and function. Mechanistically,.A-FABP interacts with CD36, and transports fatty acid. Through several experimental models, including obese mouse and in vitro endothelial cell experiments, the current project will disclose the role of A-FABP in the development of nephropathy and underlying mechanisms. Besides, the clinical samples from obesity-associated nephropathy will confirm the value of A-FABP in clinical diagnosis. Our project will declare the role of A-FABP in fatty acid transportation and obesity-associated nephropathy, and provide a novel biochemical marker for determining chronic nephropathy.

脂肪细胞脂肪酸结合蛋白（A-FABP）参与一系列肥胖诱导的并发症，但A-FABP在肥胖相关性肾病的作用仍不清楚。我们前期数据发现，A-FABP水平在肥胖小鼠肾脏组织显著升高，与肾脏病理变化呈正相关；肾脏A-FABP主要来源于内皮细胞，并介导脂肪酸的摄入；机制研究发现肾脏A-FABP与转脂蛋白CD36呈现复合体形式。因此，我们提出肾脏内皮细胞A-FABP/CD36复合体介导脂肪酸转运，进而增加局部脂质堆积，最终导致肾脏结构功能紊乱的假设。本项目中，我们拟通过肥胖小鼠模型和体外细胞实验，揭示A-FABP在肥胖相关性肾病的病理作用，并阐明A-FABP/CD36复合体调节肾脏脂肪酸转运的潜在机制。同时，我们拟通过临床样本分析，发掘A-FABP的临床预防诊断意义。项目实施将明确A-FABP作为治疗肥胖相关性肾病的新靶点，为慢性肾病的临床预防诊断提供新的分子靶标。

脂肪细胞脂肪酸结合蛋白（A-FABP）参与一系列肥胖诱导的并发症，但A-FABP在肥胖相关性肾病的作用仍不清楚。我们前期数据发现，A-FABP水平在肥胖小鼠肾脏组织显著升高，与肾脏病理变化呈正相关；肾脏A-FABP主要来源于内皮细胞，并介导脂肪酸的摄入。因此，本项目通过以下5个方面明确A-FABP在肥胖相关性肾病中的病理意义：1）利用A-FABP特异性抑制剂BMS-309403治疗肥胖小鼠，明确了A-FABP抑制剂对肥胖相关肾病的治疗作用。2）利用体外细胞实验，确证肾内皮细胞A-FABP的脂肪酸转运作用，进而阐述了潜在的分子机制。3）探讨A-FABP药理性抑制剂对脂毒性肾损伤的保护作用。4）明确肾脏内皮细胞A-FABP在高脂饮食介导的肾损伤病理过程中的意义。5）利用临床样本，探讨了血清A-FABP与肾病临床病理指标的相关性。通过前期的工作，我们首次提出并证实阻断肾脏内皮细胞 A-FABP 对肥胖相关性肾病的保护作用。机制方面，内皮细胞A-FABP介导游离脂肪酸在肾组织摄入及堆积。更重要的是，项目成果建立了 A-FABP 作为诊断代谢性肾脏病的辅助指标，为 A-FABP成为预防及诊断代谢性肾病指标提供了理论支持。总之，本研究成果对于防治肥胖相关性肾病具有重要价值，有效的临床推广应用能够为国家大健康事业做出贡献。