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.
Noha F Hassan  1 ,  Mona R El-Ansary  2 ,  Heba Mohammed Refat M Selim  3 ,  Mona S Ousman  4 ,  Marwa S Khattab  5 ,  Mahmoud R M El-Ansary  6 ,  Enas S Gad  7 ,  Suzan M M Moursi  8 ,  Asmaa Gohar  9 ,  Ayah M H Gowifel  10
Affiliations
  • 1. Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: [email protected].
  • 2. Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: [email protected].
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt. Electronic address: [email protected].
  • 4. Emergency Medical Services, College of Applied Sciences, AlMaarefa University, P.O. Box 71666, Riyadh, Saudi Arabia. Electronic address: [email protected].
  • 5. Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza 1211, Egypt. Electronic address: [email protected].
  • 6. Medical Microbiology and Immunology Department, Faculty of Medicine, Misr University for Science and Technology (MUST), Giza 12566, Egypt. Electronic address: [email protected].
  • 7. Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; Department of Pharmacology and Toxicology, faculty of Pharmacy, Sinai University-Kantara branch, Ismailia, Egypt.
  • 8. Medical Physiology Department, Faculty of Medicine, Zagazig University, 44519, Egypt. Electronic address: [email protected].
  • 9. Microbiology and Immunology Department, Faculty of Pharmacy, Ahram Canadian University, sixth of October city, Giza, Egypt; Microbiology and Immunology Department, Faculty of Pharmacy, Galala University, New Galala City, Suez, 43713, Egypt. Electronic address: [email protected].
  • 10. Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: [email protected].
PMID: 38889644 DOI: 10.1016/j.biopha.2024.116929
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.
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