Macrophage as a therapeutic target for chronic kidney diseases

通常在所有肾脏疾病进展期间观察到巨噬细胞蓄积，并可能参与疾病进展时观察到的临床组织病理学异常的发生。这些发现表明，巨噬细胞可能是慢性肾脏疾病的重要治疗靶点，尽管它们在肾脏病变部位的作用仍有待阐明。本研究采用肾活检组织、实验模型和培养体系研究活化巨噬细胞介导的肾损伤机制。我们对活化的巨噬细胞的研究表明，不同的巨噬细胞表型（M1和M2）参与慢性肾小球肾炎，在不同的阶段和病变中发挥特定的作用。M1激活的巨噬细胞（一种促炎表型）似乎在急性肾小球损伤中发挥作用，并在活动性肾小球病变（如细胞性肾小球新月体和肾小球细胞增殖）中检测到，并受到糖皮质激素的抑制。相比之下，M2激活表型（一种抗炎表型）在慢性病变（例如肾小球硬化病变和间质纤维化）部位更为主要，并且更容易被糖皮质激素激活。因此，巨噬细胞表型特异性靶向、治疗时机和治疗剂的选择对于预防巨噬细胞介导的肾损伤至关重要。

Macrophage accumulation typically observed during progression of all kidney diseases and is potentially involved in the development of clinico-histopathological abnormalities observed as the disease progresses. These findings suggest that macrophages could be an important therapeutic target for chronic kidney diseases although their roles at the site of kidney lesion remain to be elucidated. We studied the mechanism of activated macrophage-mediated kidney injury using renal biopsy tissue, experimental model and culture system. Our studies on activated macrophages revealed that different macrophage phenotypes (M1 and M2) are involved in chronic glomerulonephritis with specific roles in different phases and lesions. The M1-activated macrophage, a pro-inflammatory phenotype, appeared to play a role in acute glomerular injury and was detected in active glomerular lesions such as cellular glomerular crescents and glomerular cell proliferations, and was suppressed by glucocorticoids. In contrast, the M2-activated phenotype, an anti-inflammatory phenotype, was more predominant in sites with chronic lesions such as glomerular sclerotic lesions and interstitial fibrosis, and was rather activated by glucocorticoids. Thus, macrophage phenotype-specific targeting, timing of treatment, and choice of therapeutic agents are vital in the prevention of macrophage-mediated renal injury.