Adenosine kinase inhibition attenuates ischemia reperfusion-induced acute kidney injury
Adenosine kinase inhibition attenuates ischemia reperfusion-induced acute kidney injury
复制标题
腺苷激酶抑制可减轻缺血再灌注引起的急性肾损伤
DOI：
10.1016/j.lfs.2020.117972
复制
发表时间：
2020-09-01
期刊：
影响因子：
6.1
通讯作者：
Yuan, Yanggang
中科院分区：
文献类型：
--
作者：
Cao, Wei;Wan, Huiting;Yuan, Yanggang
急性肾损伤（阿基）发病率和死亡率高，目前尚无针对性的治疗方法。阿基的主要原因之一是缺血再灌注（IR）。在压力和缺氧条件下腺苷的释放增加，发挥抗炎和抗氧化作用。腺苷激酶（Adenosine kinase，ADK）是细胞内清除腺苷的重要酶，能维持细胞内低浓度的腺苷。我们前期的研究表明，腺苷激酶抑制剂ABT-702预处理能明显减轻顺铂在体内和体外引起的肾毒性。本研究旨在研究ADK抑制对IR诱导的阿基的影响。结果显示，ADK表达与肾小管损伤程度呈正相关，提示ADK抑制程度反映了急性肾小管坏死的严重程度。在体内，ADK抑制剂可减轻IR引起的肾损伤，其机制可能与增加组织腺苷水平、抑制氧化应激、减少细胞凋亡有关。二氯化钴（CoCl 2）可增加HK 2细胞氧化应激水平，上调促炎因子的产生，诱导细胞凋亡，抑制ADK可减轻上述损伤作用。此外，ADK抑制剂的抗凋亡作用不依赖于肌苷。总之，我们的结果支持ADK抑制对IR诱导的阿基具有保护作用的观点。腺苷激酶抑制可能为阿基的预防和治疗提供新的靶点。
Acute kidney injury (AKI) has a high morbidity and mortality, and there is no targeted treatment yet. One of the main causes of AKI is ischemia-reperfusion (IR). Increased release of adenosine under stress and hypoxia exerts anti-inflammatory and antioxidant effects. Adenosine kinase (ADK) is an important enzyme that eliminates adenosine in cells, and can maintain low adenosine concentration in cells. Our previous studies have shown that pretreatment of adenosine kinase inhibitor ABT-702 could markedly attenuate cisplatin-induced nephrotoxicity both in vivo and in vitro. This study is designed to investigate the effect of ADK inhibition on IR-induced AKI. The results showed that ADK expression was positively correlated with the degree of renal tubular injury, which suggested that the degree of ADK inhibition reflected the severity of acute tubular necrosis. In vivo, ADK inhibitor could reduce IR-induced renal injury, which might play a protective role by increasing tissue adenosine level, inhibiting oxidative stress, and reducing cell apoptosis. In HK2 cells, cobaltous dichloride (CoCl2) increased the level of oxidative stress, up-regulated the production of pro-inflammatory factor, and induced apoptosis, ADK inhibition could alleviate the above damaging effects. Moreover, the anti-apoptotic effect exerted by ADK inhibition was independent of inosine. In summary, our results support the idea that ADK inhibition has protective effects on IR-induced AKI. Adenosine kinase inhibition might provide a new target for AKI prevention and treatment.