Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation
Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation
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胰岛素样生长因子结合蛋白7通过减轻聚ADP核糖聚合酶1降解促进急性肾损伤
DOI：
10.1016/j.kint.2022.05.026
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Yon
中科院分区：
文献类型：
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作者：
Ju-tao Yu;Xiao-wei Hu;Qin Yang;Run-run Shan;Yao Zhang;Ze-hui Dong;Hai-di Li;Jia-nan Wang;Chao Li;Shuai-shuai Xie;Yu-hang Dong;Wei-jian Ni;Ling Jiang;Xue-qi Liu;Biao Wei;Jia-gen Wen;Ming-ming Liu;Qi Chen;Ya-ru Yang;Gui-yang Zhang;Hong-mei Zang;Juan Jin;Yon
新型生物标志物胰岛素样生长因子结合蛋白7（IGFBP 7）在临床上用于预测不同类型的急性肾损伤（阿基），并作为尿液生物标志物引起了极大的关注。然而，作为阿基患者循环中的一种分泌蛋白，目前尚不清楚IGFBP 7是否在阿基进展中起关键调节作用，以及其上调的机制是否仍需确定。在这里，我们发现IGFBP 7在阿基患者和小鼠的血液和尿液中高度表达，可能通过c-Jun依赖性机制，并且与肾功能障碍正相关。在顺铂、肾缺血/再灌注和脂多糖诱导的阿基小鼠模型中，IGFBP 7的整体敲除改善了肾功能障碍、炎症反应和程序性细胞死亡。IGFBP 7主要来源于肾小管上皮细胞。从肾脏中有条件地敲除IGFBP 7可保护免受阿基。相比之下，在IGFBP 7敲除小鼠中拯救IGFBP 7表达恢复了肾损伤和炎症。使用重组IGFBP 7蛋白、IGFBP 7敲低或过表达在体外测定IGFBP 7功能。另外，发现IGFBP 7结合聚[ADP-核糖聚合酶1（PARP 1）并通过拮抗E3泛素连接酶环指蛋白4（RNF 4）来抑制其降解。因此，循环中的IGFBP 7通过抑制RNF 4/PARP 1介导的肾小管损伤和炎症而充当阿基的生物标志物和关键介质。因此，IGFBP 7/PARP 1轴的过度激活代表了阿基治疗的有希望的靶标。
The novel biomarker, insulin-like growth factor binding protein 7 (IGFBP7), is used clinically to predict different types of acute kidney injury (AKI) and has drawn significant attention as a urinary biomarker. However, as a secreted protein in the circulation of patients with AKI, it is unclear whether IGFBP7 acts as a key regulator in AKI progression, and if mechanisms underlying its upregulation still need to be determined. Here we found that IGFBP7 is highly expressed in the blood and urine of patients and mice with AKI, possibly via a c-Jun-dependent mechanism, and is positively correlated with kidney dysfunction. Global knockout of IGFBP7 ameliorated kidney dysfunction, inflammatory responses, and programmed cell death in murine models of cisplatin-, kidney ischemia/reperfusion-, and lipopolysaccharide-induced AKI. IGFBP7 mainly originated from kidney tubular epithelial cells. Conditional knockout of IGFBP7 from the kidney protected against AKI. By contrast, rescue of IGFBP7 expression in IGFBP7-knockout mice restored kidney damage and inflammation. IGFBP7 function was determined in vitro using recombinant IGFBP7 protein, IGFBP7 knockdown, or overexpression. Additionally, IGFBP7 was found to bind to poly [ADP-ribose polymerase 1 (PARP1) and inhibit its degradation by antagonizing the E3 ubiquitin ligase ring finger protein 4 (RNF4). Thus, IGFBP7 in circulation acts as a biomarker and key mediator of AKI by inhibiting RNF4/PARP1-mediated tubular injury and inflammation. Hence, over-activation of the IGFBP7/PARP1 axis represents a promising target for AKI treatment.