慢性肾功能不全对单核巨噬细胞线粒体再生的影响及信号途径－代谢性炎症的潜在新机制

Inflammation is one of the characteristic features in patients with chronic renal failure, which is closely linked to several complications under the condition such as cardiovascular disease, insulin resistance, and malnutrition. Thus, chronic inflammation represents not only as a risk factor, but also a target for therapy in chronic renal failure. However, the source and triggers for inflammation in the setting of chronic kidney disease remains largely unknown. .Recent evidence suggests that immunity and energy metabolism can be interrelated at the macrophage level. Under the condition of metabolic syndrome, macrophages accumulate in adipose tissue and vessels and are in a pro-inflammatory state. The interaction between metabolic factors and activation of macrophage is designated as meta-inflammation. Several factors such as free fatty acid, oxidized low density lipoprotein, and advanced oxidation protein products have been demonstrated to activate macrophage via serine/threonine kinases inhibitor of κB kinase. In particular, free fatty acid, an important nutritional compound, can trigger the activation of macrophage via toll like receptor, thus providing a link between energy metabolism with inflammation and immunity. Indeed, rodent model deficient in regulator of fatty acid oxidation and mitochondrial capacity have an increased propensity for developing lipid-induced inflammation. .Recent literature highlights the importance not only of the number of infiltrated macrophage, but also their phenotype of activation in the maintenance of the inflammation state. There are two important subpopulations of activated macrophage with different functions, the classically (M1) and the alternatively (M2) activated macrophages. The former are considered pro-inflammatory and the latter anti-inflammatory. The determinants of their speciation are incompletely understood. Several lines of evidence showed a highly structured transcriptional network couples mitochondrial biogenesis and counter-inflammation. Enhance mitochondrial biogenesis is closely associated with activation of M2 macrophage and reduced inflammation. .Our previous studies have shown that increased lipolysis and inflammation in white adipose tissue. In the present study, we propose that impaired mitochondrial biogenesis may be an important mechanism for imbalanced activation of M1 and M2 macrophage, leading to persistent inflammation in chronic kidney disease. We will determine the mitochondrial biogenesis and number of M1 and M2 macrophage derived from peritoneal cavity and bone marrow in rats with 5/6 nephrectomy, a model of chronic renal failure. In addition, we will also treat the rats with the agonist for mitochondrial biogenesis to evaluate the effect on the activation of M1 and M2 macrophage.

由代谢相关因素如游离脂肪酸、氧化白蛋白等促发的炎症，称为代谢性炎症，是慢性肾脏病易患心血管疾病的重要机制。单核－巨噬细胞在炎症反应的发生、发展中发挥重要作用，经典和替代活化是单核－巨噬细胞活化的两种途径，分别发挥促炎和抗炎作用。经典和替代活化失衡可能与慢性炎症反应有密切关系。在前个国家自然科学基金的资助下，我们发现脂肪组织脂质分解明显增强，并伴有巨噬细胞浸润，脂肪组织炎症反应与循环中促炎症因子增多密切相关。基于这些结果，本课题提出新假设：慢性肾功能不全通过抑制AMPK-PGC1信号传导途径，损害巨噬细胞线粒体再生，导致细胞对代谢性因素刺激敏感并向促炎症表型转化。我们将检测慢性肾功能不全大鼠外周和骨髓来源单核－巨噬细胞表型、线粒体含量和功能、及与线粒体再生相关的信号分子活性，验证单核巨噬细胞线粒体再生障碍可能是代谢性炎症的关键机制，为慢性肾脏病心血管并发症寻找新的治疗靶点。

炎症是慢性肾脏病的主要特征之一，与慢性肾脏病进展及其并发症的发生、发展密切相关。巨噬细胞活化是炎症发生、发展的重要环节。本课题主要探讨慢性肾脏病对巨噬细胞活化的影响及机制，观察了慢性肾脏病大鼠模型巨噬细胞活化情况，结果发现，慢性肾脏病大鼠巨噬细胞向M1型巨噬细胞活化的能力明显增强，而向M2型活化的能力受到抑制；该效应与线粒体再生障碍密切相关；进一步的机制研究发现AMPK－PCG信号通路活性抑制与慢性肾脏病巨噬细胞活化异常密切相关。慢性肾脏病大鼠腹腔来源巨噬细胞对游离脂肪酸诱导的炎症反应明显增强，低浓度的游离脂肪酸可诱导巨噬细胞过度活化，因此在脂肪组织炎症活化的发生、发展过程中发挥重要作用。此外，我们还观察了受损肾小管上皮外泌体对巨噬细胞活化的影响，结果发现损伤肾小管上皮细胞分泌的外秘体可诱导巨噬细胞向M1型促炎症表现分化，该效应伴随SOCS1-MicroRNA-165表达异常。以上结果已发表SCI收录论文1篇（IF，4.6），中华肾脏病杂志论著1篇，另1篇SCI收录论文正在进行返修。我们的结果为慢性肾脏病炎症和代谢异常的干预提供了治疗靶点。