Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
Biomed Pharmacother. 2024 Aug;177:116929. doi: 10.1016/j.biopha.2024.116929. Epub 2024 Jun 17.
Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1β, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.
急性肾损伤 (AKI) 是脓毒症的毁灭性后果，伴有高死亡率。有研究表明，炎症途径与脂多糖 (LPS) 诱导的 AKI 的发病机制密切相关。炎症信号包括 PCSK9、HMGB1/RAGE/TLR4/MYD88/NF-κB、NLRP3/caspase-1 和 Fractalkine/CX3CR1，被认为是这一环节的主要先驱。Alirocumab，PCSK9 抑制剂，具有显著的抗炎特性。因此，本研究旨在阐明 Alirocumab 对体外大肠杆菌的抗菌作用。此外，评估 Alirocumab 对 LPS 诱导的 AKI 大鼠的潜在肾保护作用，强调这些有益作用涉及的潜在机制。36 只成年雄性 Wistar 大鼠被分为三组（n=12）。第 I 组为正常对照组，第 II 和 III 组于第 16 天通过单次腹腔注射 LPS 诱导脓毒症介导的 AKI。第 III 组给予 Alirocumab。结果表明，Alirocumab 减轻了 LPS 诱导的 AKI，表现在肾功能试验（肌酐、胱抑素 C、KIM-1 和 NGAL）、氧化应激生物标志物（Nrf2、HO-1、TAC 和 MDA）、凋亡标志物和肾脏组织病理学发现的改善。此外，Alirocumab 明显抑制了 LPS 介导的炎症反应，通过降低 HMGB1、TNF-α、IL-1β 和 caspase-1 含量、PCSK9、RAGE、NF-ᴋB 和 Fractalkine/CX3CR1 的基因表达以及 TLR4、MYD88 和 NLRP3 的 mRNA 表达来证实。关于抗菌作用，结果表明 Alirocumab 对致病性革兰氏阴性大肠杆菌具有潜在的抗菌活性。总之，Alirocumab 通过调节 Nrf2/HO-1、PCSK9、HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1、Fractalkine/CX3R1 和凋亡轴，对 LPS 诱导的 AKI 发挥了肾保护作用。
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