Effects of Liposome Clodronate on Renal Leukocyte Populations and Renal Fibrosis in Murine Obstructive Nephropathy
Effects of Liposome Clodronate on Renal Leukocyte Populations and Renal Fibrosis in Murine Obstructive Nephropathy
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DOI：
10.1254/jphs.09227fp
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Miura, Katsuyuki
中科院分区：
文献类型：
--
作者：
Kitamoto, Koichiro;Machida, Yuichi;Miura, Katsuyuki
尽管脂质体包封的氯膦酸盐已被用作从某些组织中消耗巨噬细胞的手段，但在正常和病理条件下，肾脏内的靶白细胞亚型尚不清楚。因此，本研究进行检查脂质体氯膦酸盐对肾浸润细胞类型的影响，单侧输尿管梗阻（UUO），并试图将这些变化与肾纤维化的早期发展机制。采用流式细胞术分析梗阻肾细胞悬液，测定肾浸润白细胞亚型和计数。持续5天的UUO引起肾小管凋亡和肾纤维化，并显示肾白细胞（包括单核细胞/巨噬细胞、树突状细胞和T细胞）增加4倍。重复给予脂质体氯膦酸盐可选择性地耗竭阻塞和非阻塞肾脏中的F4/80（+）单核细胞/巨噬细胞和F4/80（+）树突细胞，但不耗竭F4/80（-）树突细胞或其他细胞类型。脂质体氯膦酸钠还能显著减轻肾小管细胞凋亡和肾纤维化。在阻塞的肾脏中观察到的TNF-α和TGF-β基因表达的增加通过消耗肾脏单核吞噬细胞而显著减弱。这些发现表明，F4/80（+）单核细胞/巨噬细胞和/或F4/80（+）树突状细胞在梗阻诱导的肾小管凋亡和肾纤维化的发展中发挥关键作用，可能通过TNF-α和TGF-β依赖性机制。
Although liposome-encapsulated clodronate has been used as a means to deplete macrophages from certain tissues, target leukocyte subtypes within the kidney are not clearly known under normal and pathologic conditions. The present study was therefore conducted to examine the effects of liposome clodronate on renal infiltrating cell type following unilateral ureteral obstruction (UUO) and tried to correlate these changes to the mechanisms of early development of renal fibrosis. Renal infiltrating leukocyte subtypes and Counts were determined by using multicolor flow cytometric analysis of cell suspensions from obstructed kidneys. UUO for 5 days elicited renal tubular apoptosis and renal fibrosis and showed 4-fold increase in renal leukocytes including monocytes/macrophages, dendritic cells, and T-cells. Repeated administration of liposome clodronate selectively depleted F4/80(+) monocytes/macrophages and F4/80(+) dendritic cells but not F4/80(-) dendritic cells or other cell types in both obstructed and non-obstructed kidneys. Tubular apoptosis and renal fibrosis were also significantly attenuated by liposome clodronate. Increased gene expression of TNF-alpha and TGF-beta observed in obstructed kidneys were markedly attenuated by depletion of renal mononuclear phagocytes. These findings suggest that F4/80(+) monocytes/macrophages and/or F4/80(+) dendritic cells play a pivotal role in the development of obstruction-induced tubular apoptosis and renal fibrosis, possibly through TNF-alpha and TGF-beta dependent mechanisms.