传出细胞增多
细胞生物学
细胞凋亡
炎症
急性肾损伤
吞噬作用
化学
医学
免疫学
癌症研究
生物
巨噬细胞
内科学
生物化学
体外
作者
R. Gandhi,James Yi,Jihyen Ha,Hang Shi,Ola Z. Ismail,Sahra Nathoo,Joseph V. Bonventre,Xizhong Zhang,Lakshman Gunaratnam
出处
期刊:American Journal of Physiology-renal Physiology
[American Physical Society]
日期:2014-05-15
卷期号:307 (2): F205-F221
被引量:35
标识
DOI:10.1152/ajprenal.00638.2013
摘要
Efficient clearance of apoptotic cells (efferocytosis) prevents inflammation and permits repair following tissue injury. Kidney injury molecule-1 (KIM-1) is a receptor for phosphatidylserine, an "eat-me" signal exposed on the surface of apoptotic cells that marks them for phagocytic clearance. KIM-1 is upregulated on proximal tubule epithelial cells (PTECs) during ischemic acute kidney injury (AKI), enabling efferocytosis by surviving PTECs. KIM-1 is spontaneously cleaved at its ectodomain region to generate a soluble fragment that serves a sensitive and specific biomarker for AKI, but the biological relevance of KIM-1 shedding is unknown. Here, we sought to determine how KIM-1 shedding might regulate efferocytosis. Using cells that endogenously and exogenously express KIM-1, we found that hydrogen peroxide-mediated oxidative injury or PMA treatment accelerated KIM-1 shedding in a dose-dependent manner. KIM-1 shedding was also accelerated when apoptotic cells were added. Accelerated shedding or the presence of excess soluble KIM-1 in the extracellular milieu significantly inhibited efferocytosis. We also identified that TNF-α-converting enzyme (TACE or ADAM17) mediates both the spontaneous and PMA-accelerated shedding of KIM-1. While accelerated shedding inhibited efferocytosis, we found that spontaneous KIM-1 cleavage does not affect the phagocytic efficiency of PTECs. Our results suggest that KIM-1 shedding is accelerated by worsening cellular injury, and excess soluble KIM-1 competitively inhibits efferocytosis. These findings may be important in AKI when there is severe cellular injury.
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