Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Instituto Sírio-Libanês de Ensino e Pesquisa, Hospital Sírio-Libanês, Sao Paulo, Brazil.
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Int Immunopharmacol. 2018 Nov;64:151-161. doi: 10.1016/j.intimp.2018.08.020. Epub 2018 Aug 31.
Acute kidney injury (AKI) and chronic kidney disease (CKD) are major concerns in worldwide public health, and their pathophysiology involves immune cells activation, being macrophages one of the main players of both processes. It is suggested that metabolic pathways could contribute to macrophage modulation and phosphatidylinositol‑3 kinase (PI3K) pathway was shown to be activated in kidneys subjected to ischemia and reperfusion as well as unilateral ureteral obstruction (UUO). Although PI3K inhibition is mostly associated with anti-inflammatory response, its use in kidney injuries has been shown controversial results, which indicates the need for further studies. Our aim was to unveil the role of PI3Kγ in macrophage polarization and in kidney diseases development. We analyzed bone-marrow macrophages polarization from wild-type (WT) and PI3Kγ knockout (PI3K KO) animals. We observed increased expression of M1 (CD86, CCR7, iNOS, TNF, CXCL9, CXCL10, IL-12 and IL-23) and decreased of M2 (CD206, Arg-1, FIZZ1 and YM1) markers in the lack of PI3Kγ. And this modulation was accompanied by higher levels of inflammatory cytokines in PI3K KO M1 cells. PI3K KO mice had increased M1 in steady state kidneys, and no protection was observed in these mice after acute and chronic kidney insults. On the contrary, they presented higher levels of protein-to-creatinine ratio and Kim-1 expression and increased tubular injury. In conclusion, our findings demonstrated that the lack of PI3Kγ favors M1 macrophages polarization providing an inflammatory-prone environment, which does not prevent kidney diseases progression.
急性肾损伤 (AKI) 和慢性肾脏病 (CKD) 是全球公共卫生的主要关注点，其病理生理学涉及免疫细胞的激活，巨噬细胞是这两个过程的主要参与者之一。有研究表明代谢途径可能有助于巨噬细胞的调节，并且已经证实磷脂酰肌醇 3 激酶 (PI3K) 途径在缺血再灌注和单侧输尿管梗阻 (UUO) 引起的肾脏中被激活。尽管 PI3K 抑制大多与抗炎反应有关，但在肾脏损伤中的应用已显示出有争议的结果，这表明需要进一步研究。我们的目的是揭示 PI3Kγ 在巨噬细胞极化和肾脏疾病发展中的作用。我们分析了来自野生型 (WT) 和 PI3Kγ 敲除 (PI3K KO) 动物的骨髓巨噬细胞极化。我们观察到缺乏 PI3Kγ 时，M1（CD86、CCR7、iNOS、TNF、CXCL9、CXCL10、IL-12 和 IL-23）标志物的表达增加，而 M2（CD206、Arg-1、FIZZ1 和 YM1）标志物的表达减少。这种调节伴随着 PI3K KO M1 细胞中炎症细胞因子水平的升高。PI3K KO 小鼠在稳态肾脏中具有更多的 M1，并且在急性和慢性肾损伤后这些小鼠没有得到保护。相反，它们表现出更高的蛋白/肌酐比值和 Kim-1 表达以及增加的肾小管损伤。总之，我们的研究结果表明，缺乏 PI3Kγ 有利于 M1 巨噬细胞的极化，提供了一种易发生炎症的环境，这并不能阻止肾脏疾病的进展。
