Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs

Biomed Pharmacother. 2024 Aug:177:116929. doi: 10.1016/j.biopha.2024.116929. Epub 2024 Jun 17.

Abstract

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.

Keywords: Alirocumab; Fractalkine /CX3R1; HMGB1/RAGE/TLR4/ MYD88/NF-ᴋB/NLRP3/Caspase-1; Kidney; LPS; PCSK9.

MeSH terms

  • Acute Kidney Injury* / chemically induced
  • Acute Kidney Injury* / drug therapy
  • Acute Kidney Injury* / metabolism
  • Acute Kidney Injury* / pathology
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Antibodies, Monoclonal, Humanized* / pharmacology
  • Antioxidants* / pharmacology
  • CX3C Chemokine Receptor 1* / metabolism
  • Chemokine CX3CL1* / metabolism
  • Disease Models, Animal
  • HMGB1 Protein* / metabolism
  • Heme Oxygenase (Decyclizing)* / metabolism
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Lipopolysaccharides
  • Male
  • NF-E2-Related Factor 2* / metabolism
  • NF-kappa B* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Oxidative Stress / drug effects
  • PCSK9 Inhibitors
  • Proprotein Convertase 9 / genetics
  • Proprotein Convertase 9 / metabolism
  • Rats
  • Rats, Wistar*
  • Sepsis* / complications
  • Sepsis* / drug therapy
  • Sepsis* / metabolism
  • Signal Transduction* / drug effects

Substances

  • HMGB1 Protein
  • Chemokine CX3CL1
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Hbp1 protein, rat
  • Nlrp3 protein, rat
  • Hmox1 protein, rat
  • alirocumab
  • Heme Oxygenase (Decyclizing)
  • Antibodies, Monoclonal, Humanized
  • NF-kappa B
  • NF-E2-Related Factor 2
  • Antioxidants
  • PCSK9 protein, rat
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, rat
  • Nfe2l2 protein, rat
  • Lipopolysaccharides
  • Cx3cl1 protein, rat
  • PCSK9 Inhibitors
  • Proprotein Convertase 9
  • Anti-Inflammatory Agents