Renalase peptides reduce pancreatitis severity in mice.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI:10.1152/ajpgi.00143.2024
Thomas R Kolodecik, Xiaoyu Guo, Christine A Shugrue, Xiaojia Guo, Gary V Desir, Li Wen, Fred Gorelick
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Abstract

Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development.NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.

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肾酶肽减轻小鼠胰腺炎的严重程度
急性胰腺炎是胰腺的一种急性炎症损伤,目前尚无特效疗法。循环蛋白肾酶由肾脏和其他组织产生,具有强大的抗炎和促生存特性。重组肾酶可减轻轻度胰腺炎的严重程度;其活性包含在一个保守的 20 aa 肾酶位点(RP220)中。在此,我们使用两种临床相关的急性胰腺炎模型研究了肾酶对胰腺炎的治疗效果。我们研究了含有 RP220 位点的多肽在急性胰腺炎后一天和两天的严重脑啡肽诱导的小鼠中减轻损伤的能力。肾酶肽的初始剂量是在发病前或发病后给予的。收集样本以确定早期胰腺炎反应(组织水肿、血浆淀粉酶、活性酶原)以及后期组织损伤和炎症变化。在两种临床前模型中,肾酶肽都能显著减轻与胰腺炎相关的组织损伤,尤其是炎症、坏死和整体损伤。使用特异性免疫组化标记物对炎症进行量化显示,肾酶肽在两种模型中都能显著减少骨髓源性炎症以及中性粒细胞和巨噬细胞的数量。在重度胰胆素模型中,无论是否进行预处理,使用肾酶肽都能显著减轻损伤。胰腺炎和肾酶肽对雌性和雄性小鼠的影响似乎相同。这些研究表明,肾酶肽保留了重组肾酶的抗炎和促生存特性,能减轻急性胰腺炎的严重程度,可能成为有吸引力的候选治疗药物。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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