Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
ICU, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, China.
FASEB J. 2020 Dec;34(12):16307-16318. doi: 10.1096/fj.201902943R. Epub 2020 Oct 21.
Postischemic acute kidney injury (AKI) is a common clinical complication and often fatal, with no effective treatment available. Little is known about the role of leukocytes trapped in renal vessels during ischemia-reperfusion injury (IRI) in the postischemic AKI. We designed a new animal model in rats with preforming renal artery lavage prior to IRI to investigate the effect of diminishing the residual circulating leukocytes on kidney damage and inflammation. Moreover, the functional changes of macrophages in hypoxia reoxygenation condition were also analyzed. We found pre-ischemic renal lavage significantly decreased the serum creatinine and blood urea nitrogen levels, and downregulated the mRNA and protein expressions in kidneys and urinary secretion of kidney injury molecule-1 of rats after IRI. The renal pathological damage caused by IRI was also ameliorated by pre-ischemic renal lavage, as evidenced by fewer cast formation, diminished morphological signs of AKI in the tissue at 24 hours after IRI. Pre-ischemic renal lavage reduced the numbers of infiltrating CD68 macrophages and MPO neutrophils. The mRNA expression of pro-inflammatory mediator in IRI kidneys and the levels of pro-inflammatory cytokines in circulatory system and urine were also reduced due to pre-ischemic lavage. Compared with nontreated rats with IRI, pre-ischemic renal lavage significantly reduced the phosphorylation levels of ERK and p65 subunit of NF-κB in the kidney after IRI. In addition, we found hypoxia/reoxygenation could promote the expression of pro-inflammatory mediators and inhibit the expression of anti-inflammatory factors by regulating ERK/NF-κB signaling pathway. Thus, pre-ischemic renal lavage could clearly reduce the renal damage after IRI by attenuating inflammation, and macrophages trapped in renal vessels during IRI could be important pathogenic factors driving tissue injury.
缺血后急性肾损伤（AKI）是一种常见的临床并发症，常导致死亡，目前尚无有效的治疗方法。缺血再灌注损伤（IRI）期间肾血管中被困白细胞在缺血后 AKI 中的作用知之甚少。我们设计了一种新的大鼠动物模型，在 IRI 前进行肾动脉灌洗，以研究减少循环残留白细胞对肾脏损伤和炎症的影响。此外，还分析了巨噬细胞在缺氧复氧条件下的功能变化。我们发现，缺血前肾灌洗可显著降低 IRI 后大鼠血清肌酐和血尿素氮水平，并下调肾脏和尿中肾损伤分子 1 的 mRNA 和蛋白表达。缺血前肾灌洗还可减轻 IRI 引起的肾脏病理损伤，表现为 IRI 后 24 小时组织中 casts 形成减少，AKI 形态学征象减轻。缺血前肾灌洗减少了浸润的 CD68 巨噬细胞和 MPO 中性粒细胞的数量。IRI 肾脏中促炎介质的 mRNA 表达以及循环系统和尿液中促炎细胞因子的水平也因缺血前灌洗而降低。与未治疗的 IRI 大鼠相比，缺血前肾灌洗可显著降低 IRI 后肾脏中 ERK 和 NF-κB p65 亚基的磷酸化水平。此外，我们发现，通过调节 ERK/NF-κB 信号通路，缺氧/复氧可促进促炎介质的表达，抑制抗炎因子的表达。因此，缺血前肾灌洗可通过减轻炎症明显减轻 IRI 后的肾脏损伤，IRI 期间被困在肾血管中的巨噬细胞可能是驱动组织损伤的重要致病因素。
