Pretreatment with a novel Toll-like receptor 4 agonist attenuates renal ischemia-reperfusion injury.

IF 3.7 2区 医学 Q1 PHYSIOLOGY
Antonio Hernandez, Naeem K Patil, Maya Brewer, Rachel Delgado, Lauren Himmel, Lauren N Lopez, Julia K Bohannon, Allison M Owen, Edward R Sherwood, Mark P de Caestecker
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Abstract

Acute kidney injury (AKI) is common in surgical and critically ill patients. This study examined whether pretreatment with a novel Toll-like receptor 4 agonist attenuated ischemia-reperfusion injury (IRI)-induced AKI (IRI-AKI). We performed a blinded, randomized-controlled study in mice pretreated with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide (PHAD), a synthetic Toll-like receptor 4 agonist. Two cohorts of male BALB/c mice received intravenous vehicle or PHAD (2, 20, or 200 µg) at 48 and 24 h before unilateral renal pedicle clamping and simultaneous contralateral nephrectomy. A separate cohort of mice received intravenous vehicle or 200 µg PHAD followed by bilateral IRI-AKI. Mice were monitored for evidence of kidney injury for 3 days postreperfusion. Kidney function was assessed by serum blood urea nitrogen and creatinine measurements. Kidney tubular injury was assessed by semiquantitative analysis of tubular morphology on periodic acid-Schiff (PAS)-stained kidney sections and by kidney mRNA quantification of injury [neutrophil gelatinase-associated lipocalin (Ngal), kidney injury molecule-1 (Kim-1), and heme oxygenase-1 (Ho-1)] and inflammation [interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (Tnf-α)] using quantitative RT-PCR. Immunohistochemistry was used to quantify proximal tubular cell injury and renal macrophages by quantifying the areas stained with Kim-1 and F4/80 antibodies, respectively, and TUNEL staining to detect the apoptotic nuclei. PHAD pretreatment yielded dose-dependent kidney function preservation after unilateral IRI-AKI. Histological injury, apoptosis, Kim-1 staining, and Ngal mRNA were lower in PHAD-treated mice and IL-1β mRNA was higher in PHAD-treated mice. Similar pretreatment protection was noted with 200 mg PHAD after bilateral IRI-AKI, with significantly reduced Kim-1 immunostaining in the outer medulla of mice treated with PHAD after bilateral IRI-AKI. In conclusion, PHAD pretreatment leads to dose-dependent protection from renal injury after unilateral and bilateral IRI-AKI in mice.NEW & NOTEWORTHY Pretreatment with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide; a novel synthetic Toll-like receptor 4 agonist, preserves kidney function during ischemia-reperfusion injury-induced acute kidney injury.

新型toll样受体4激动剂预处理可减轻肾缺血再灌注损伤。
急性肾损伤(AKI)常见于外科和危重病人。本研究探讨了一种新型toll样受体4激动剂预处理是否能减轻缺血再灌注损伤(IRI)诱导的AKI (IRI-AKI)。我们进行了一项盲法、随机对照研究,用3-癸酰6-酰基磷酸化六酰二糖(PHAD)预处理小鼠,PHAD是一种合成的toll样受体4激动剂。两组雄性BALB/c小鼠在单侧肾蒂夹紧和同时对侧肾切除术前48和24小时静脉注射载药剂或PHAD(2、20或200µg)。另一组小鼠接受静脉注射或200µg PHAD,然后进行双侧IRI-AKI。小鼠在灌注后3天监测肾脏损伤的证据。通过测定血清尿素氮和肌酐来评估肾功能。通过半定量分析周期性酸-希夫(PAS)染色肾切片的肾小管形态,并通过定量RT-PCR定量检测肾损伤[中性粒细胞明胶酶相关脂钙素(Ngal)、肾损伤分子-1 (Kim-1)和血红素氧合酶-1 (Ho-1)]和炎症[白细胞介素-6 (IL-6)、白细胞介素-1β (IL-1β)和肿瘤坏死因子-α (Tnf-α)]的mRNA。采用免疫组化方法分别定量Kim-1和F4/80抗体染色区域,TUNEL染色检测凋亡核,定量近端小管细胞损伤和肾巨噬细胞。PHAD预处理在单侧IRI-AKI后产生剂量依赖性的肾功能保存。phad处理小鼠的组织学损伤、细胞凋亡、Kim-1染色和Ngal mRNA较低,IL-1β mRNA较高。双侧IRI-AKI后,200 mg PHAD也有类似的预处理保护作用,双侧IRI-AKI后,PHAD治疗小鼠外髓质的Kim-1免疫染色显著降低。总之,PHAD预处理对小鼠单侧和双侧IRI-AKI后肾损伤具有剂量依赖性保护作用。3-癸酰6-酰基磷酸化六酰二糖预处理一种新型合成toll样受体4激动剂,在缺血-再灌注损伤引起的急性肾损伤期间保持肾功能。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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