IL-6在临床定义的小鼠模型中介导肾前氮质血症后的肝脏急性期反应。

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-09-01 Epub Date: 2023-07-20 DOI:10.1152/ajprenal.00267.2022
Kayo Okamura, Sizhao Lu, Zhibin He, Chris Altmann, John R Montford, Amy S Li, M Scott Lucia, David J Orlicky, Mary Weiser-Evans, Sarah Faubel
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引用次数: 0

摘要

肾前氮质血症(PRA)是急性肾损伤的主要原因,在临床前模型中很少进行研究。我们试图开发并表征一种符合临床定义的新型PRA模型:肾小球滤过率(GFR)的急性损失,在复苏后恢复到基线。研究了成年雄性C57BL/6J野生型(WT)和IL-6-/-小鼠。在时间=0和3小时给予腹膜内速尿(4 mg)或赋形剂,以诱导容量损失引起的PRA。6小时开始用1mL腹腔盐水复苏,共4次,持续36小时。速尿给药6小时后,测量的肾小球滤过率为基线的25%,48小时盐水复苏后恢复到基线。PRA给药6 h后,血浆白细胞介素(IL)-6显著增加,肾和肝组织学正常,肾和肝脏乳酸正常,肾损伤分子-1免疫荧光阴性。肝脏中有327个差异调节基因上调,急性期反应是上调最显著的途径;84个上调基因(25%)在IL-6-/-小鼠中被抑制,急性期反应是最显著的抑制途径。还研究了显著上调的基因及其蛋白质,包括血清淀粉样蛋白A2、血清淀粉样蛋白质A1、脂质运载蛋白2、趋化因子(C-X-C基序)配体1和触珠蛋白;肝基因表达和血浆蛋白水平在野生型PRA中均增加,在IL-6-/-PRA中均降低。这项工作证明了先前未知的PRA的全身作用,包括IL-6介导的肝脏急性期反应的上调。新的和值得注意的是,肾前氮质血症(PRA)占急性肾损伤(AKI)病例的三分之一,但很少在临床前模型中进行研究。我们开发了一种临床定义的肾前氮质血症小鼠模型,其特征是测量的肾小球滤过率(GFR)降低75%,复苏后测量的肾小球过滤率恢复到基线,并且没有肾小管损伤。观察到许多全身效应,如血浆白细胞介素-6(IL-6)增加和肝脏急性期反应上调。
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IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model.

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

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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.
期刊最新文献
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