Synthetic and non-synthetic inhibition of ADAM10 and ADAM17 reduces inflammation and oxidative stress in LPS-induced acute kidney injury in male and female mice

Atak M., Yigit E., Huner Yigit M., Topal Suzan Z., Yilmaz Kutlu E., Karabulut S.

EUROPEAN JOURNAL OF PHARMACOLOGY, cilt.983, 2024 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 983
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1016/j.ejphar.2024.176964
  • Dergi Adı: EUROPEAN JOURNAL OF PHARMACOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Food Science & Technology Abstracts, Veterinary Science Database
  • Karadeniz Teknik Üniversitesi Adresli: Evet

Özet

Acute kidney injury (AKI) is a severe medical condition that can lead to illness and death. A disintegrin and metalloprotease (ADAM) protein family is a potential treatment target for AKI due to its involvement in inflammation, growth, and differentiation. While ADAM10 and ADAM17 have been identified as significant contributors to inflammation, it is unclear whether they play a critical role in AKI. In this study, we induced AKI in male and female mice using lipopolysaccharide, a bacterial endotoxin that causes inflammation and oxidative stress. The role of kaempferol, which is found in many natural products and known to have antioxidant and antiinflammatory activity in many pre-clinical studies, was investigated through ADAM10/17 enzymes in AKI. We also investigated the efficacy of a selective synthetic inhibitor named GW280264X for ADAM10/17 inhibition in AKI. Blood urea nitrogen and creatinine levels were measured in serum, while tumor necrosis factor-alpha, vascular adhesion molecule, interleukin (IL)-1 beta, glucose regulatory protein-78, IL-10, nuclear factor kappa-B, thiobarbituric acid reactive substances, total thiol, ADAM10, and ADAM17 levels were measured in kidney tissue. We also evaluated kidney tissue histologically using hematoxylin and eosin, periodic acid-schiff, and caspase-3 staining. This research demonstrates that GW280264X and kaempferol reduces inflammation and oxidative stress, as evidenced by biochemical and histopathological results in AKI through ADAM10/17 inhibition. These findings suggest that inhibiting ADAM10/17 may be a promising therapeutic approach for treating acute kidney injury.