利格列汀减轻脂多糖诱导的小鼠急性肾损伤：新的肾BDNF/TrkB/ nrf2依赖的抗氧化、抗炎和抗凋亡机制

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-02 DOI:10.1016/j.lfs.2025.123602

Nada M. Kamel , Sarah S. El-Sayed , Shimaa O. Ali , Rabab H. Sayed , Maheera H. Safwat

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引用次数: 0

摘要

急性肾损伤（AKI）是脓毒症的常见并发症，但目前尚无有效的治疗方法。脂多糖（LPS）诱导脓毒性AKI的主要机制是氧化应激、炎症和细胞凋亡。本研究旨在探讨利格列汀（一种抗糖尿病二肽基肽酶(DPP)-4抑制剂）对lps诱导的AKI的潜在肾保护作用，特别关注肾脑源性神经营养因子(BDNF)/核因子红细胞2相关因子2 （NRF2）轴。小鼠分为对照组、LPS组、LPS + 利格列汀组和LPS + 利格列汀+ANA-12（原肌球蛋白受体激酶B （TrkB）拮抗剂）组。我们的研究结果显示，利格列汀部分通过增强BDNF改善了AKI，这可以通过改善肾脏的组织结构和功能来证明，其中血清肌酐、血尿素氮、胱抑素C和肾损伤分子-1随着血清白蛋白的增加而降低。这些改善是由于胰高血糖素样肽-1/BDNF/ trkb介导的NRF2激活，增强了抗氧化、抗炎和抗凋亡途径。利格列汀通过增强NRF2抑制髓过氧化物酶、丙二醛、NLR家族pyrin结构域3炎性体、核因子- kappab、肿瘤坏死因子- α、单核细胞趋化蛋白-1、b细胞淋巴瘤2 （Bcl2）相关X蛋白，同时提高抗氧化谷胱甘肽和抗凋亡Bcl2含量。在利格列汀之前服用ANA-12部分逆转了这些有益作用。因此，我们的研究结果表明，利格列汀在治疗脂多糖诱导的AKI方面具有治疗潜力。此外，他们提供了对其潜在机制的见解，强调肾BDNF信号作为潜在的治疗靶点，通过下游NRF2增强及其相关的抗氧化、抗炎和抗凋亡作用。

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Linagliptin mitigates lipopolysaccharide-induced acute kidney injury in mice: Novel renal BDNF/TrkB/NRF2-dependent antioxidant, anti-inflammatory, and antiapoptotic mechanisms

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Linagliptin mitigates lipopolysaccharide-induced acute kidney injury in mice: Novel renal BDNF/TrkB/NRF2-dependent antioxidant, anti-inflammatory, and antiapoptotic mechanisms

Acute kidney injury (AKI) is a common complication associated with sepsis, yet no effective treatment is currently available. The primary mechanisms involved in lipopolysaccharide (LPS)-induced septic AKI are oxidative stress, inflammation, and apoptosis. This study aimed to investigate the potential renoprotective effects of linagliptin, an antidiabetic dipeptidyl peptidase (DPP)-4 inhibitor, against LPS-induced AKI with special emphasis on renal brain-derived neurotrophic factor (BDNF)/ nuclear factor erythroid 2-related factor 2 (NRF2) axis. Mice were divided into control, LPS, LPS + linagliptin, and LPS + linagliptin+ANA-12 (tropomyosin receptor kinase B (TrkB) antagonist) groups. Our results revealed that linagliptin, partially through BDNF augmentation, ameliorated AKI, evidenced by the improved histological structure and function of the kidney where serum creatinine, blood urea nitrogen, cystatin C, and renal kidney injury molecule-1were decreased with increased serum albumin. These improvements result from Glucagon-like peptide-1/BDNF/TrkB-mediated NRF2 activation, enhancing antioxidant, anti-inflammatory, and antiapoptotic pathways. Linagliptin, through NRF2 augmentation, suppressed renal myeloperoxidase, malondialdehyde, NLR Family pyrin domain-containing 3 inflammasome, nuclear factor-kappaB, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, B-cell lymphoma 2 (Bcl2)-associated X protein, while boosting the antioxidant glutathione and the antiapoptotic Bcl2 contents. The administration of ANA-12 before linagliptin partially reversed these beneficial effects. Accordingly, our results suggest that linagliptin has therapeutic potential in managing LPS-induced AKI. Furthermore, they provide insights into its underlying mechanisms, highlighting renal BDNF signaling as a potential therapeutic target through downstream NRF2 enhancement and its associated antioxidant, anti-inflammatory, and antiapoptotic effects.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.