Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

• Published in: International journal of molecular sciences Vol. 23; no. 23; p. 14570
• Main Authors: Abd-Ellatif, Rania Nagi, Nasef, Nahla Anas, El-Horany, Hemat El-Sayed, Emam, Marwa Nagy, Younis, Reham Lotfy, El Gheit, Rehab E Abo, Elseady, Walaa, Radwan, Doaa A, Hafez, Yasser Mostafa, Eissa, Ahmad, Aboalsoud, Alshimaa, Shalaby, Rania H, Atef, Marwa Mohamed
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23-11-2022; MDPI
• Subjects: Adrenomedullin; Adrenomedullin - pharmacology; Animal models; Animals; Antibiotics; Apoptosis; Bcl-2 protein; Caspase-1; Creatinine; Cytokines; DNA damage; Doxorubicin; Doxorubicin - toxicity; gasdermin; Gene expression; IL-1β; Immunoreactivity; Inflammation; Inflammation Mediators; Injection; Interleukin 18; Kidneys; Male; nephrotoxicity; Oxidative Stress; Pyroptosis; Rats; Rats, Wistar; Renal Insufficiency - chemically induced; Renal Insufficiency - drug therapy; Tumor necrosis factor-α; pyroptosis; gasdermin; adrenomedullin; doxorubicin; nephrotoxicity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232314570

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM's antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.