磷酸肌醇3激酶p110γ特异性抑制剂减轻小鼠肾缺血-再灌注损伤

Reduction in Renal Ischemia-Reperfusion Injury in Mice by a Phosphoinositide 3-Kinase p110gamma-Specific Inhibitor.

作者信息

Kim Nayoung, Woo Dong-Cheol, Joo Seo Jeong, Song Youyol, Lee Jae Jin, Woo Chul-Woong, Kim Sang Tae, Hong Seokmann, Cho Yong Mee, Han Duck-Jong

机构信息

1 Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 2 Department of Medicine Graduate School, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 3 Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, South Korea. 4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 5 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

出版信息

Transplantation. 2015 Oct;99(10):2070-6. doi: 10.1097/TP.0000000000000742.

DOI:10.1097/TP.0000000000000742

PMID:26431158

Abstract

BACKGROUND

Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110γ and p110δ play important roles in immune cell migration and function, we investigated the effects of PI3K p110γ- and p110δ-specific inhibitors in a murine renal IRI model.

METHODS

Renal function was assessed by serum creatine and hematoxylin-eosin staining. Immune cell migration was assessed by flow cytometry and an in vitro cell migration assay using Transwell plates. Gene expression analysis and a multiplex cytokine/chemokine assay were performed to find cytokines/chemokines whose expression was upregulated in renal IRI and affected by p110γ-specific inhibitor.

RESULTS

The PI3K p110γ-specific inhibitor, but not p110δ-specific inhibitor, significantly reduced serum creatine levels and acute tubular necrosis. These were accompanied by reduced infiltration of B cells and reduced expression of CXCL9, a CXCR3 ligand, suggesting that p110γ plays an important role in B-cell migration toward injured kidneys. An in vitro cell migration assay revealed for the first time that B-cell migration to injured kidney cells and to CXCL9 requires p110γ.

CONCLUSIONS

p110γ-specific inhibitor ameliorates renal IRI by reducing necrosis and immune cell migration. This inhibitor may have the potential to reduce renal graft failure caused by renal IRI.

摘要

背景

尽管肾缺血再灌注损伤（IRI）可导致移植肾功能延迟，但尚未有针对性的治疗方法。由于磷酸肌醇3激酶（PI3K）p110γ和p110δ在免疫细胞迁移和功能中起重要作用，我们在小鼠肾IRI模型中研究了PI3K p110γ和p110δ特异性抑制剂的作用。

方法

通过血清肌酐和苏木精-伊红染色评估肾功能。通过流式细胞术和使用Transwell板的体外细胞迁移试验评估免疫细胞迁移。进行基因表达分析和多重细胞因子/趋化因子检测，以寻找在肾IRI中表达上调且受p110γ特异性抑制剂影响的细胞因子/趋化因子。

结果

PI3K p110γ特异性抑制剂而非p110δ特异性抑制剂可显著降低血清肌酐水平并减轻急性肾小管坏死。这些变化伴随着B细胞浸润减少以及CXCR3配体CXCL9的表达降低，表明p110γ在B细胞向受损肾脏的迁移中起重要作用。体外细胞迁移试验首次揭示，B细胞向受损肾细胞和CXCL9的迁移需要p110γ。