Activation of angiotensin-converting enzyme 2 mitigates Doxorubicin induced nephrotoxicity by TLR4/NF-kB downregulation | ||
| Mansoura Journal of Forensic Medicine and Clinical Toxicology | ||
| Articles in Press, Accepted Manuscript, Available Online from 24 February 2025 | ||
| Document Type: Original Article | ||
| DOI: 10.21608/mjfmct.2025.353763.1095 | ||
| Authors | ||
| Suzan A Khodir* 1; Sara Elsayed Abdelrahman2; noha Abd El-aziz3; Yasmin M Aboul-Ela4; Sara A Khedr5; Eman A El-Sawaf6; Soha H Abd EL-Khalek7; Menna Allah I El Menyawi8; Walaa Ahmed Yusuf9; Mohamed Ahmed Greash10; Noha O Shawky11 | ||
| 1Physiology Department, Faculty of Medicine, Menoufia University, Egypt | ||
| 2Medical Biochemistry and Molecular Biology Department, Faculty of medicine, Ain Shams University, Egypt | ||
| 3Anatomy and Embryology Department, Faculty of Medicine, Menoufia University | ||
| 4Clinical Pharmacology Department, Faculty of medicine, Ain Shams University, Egypt. | ||
| 5Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Egypt | ||
| 6Anatomy and Embryology Department, Faculty of Medicine, Helwan University Egypt | ||
| 7Forensic Medicine and Clinical Toxicology department, Faculty of Medicine, Menoufia University | ||
| 8Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt | ||
| 9Pathology Department, Faculty of Medicine, Mansoura University, Egypt. | ||
| 10Internal Medicine Department, Faculty of Medicine, Suez Canal University | ||
| 11Medical Physiology Department, Faculty of Medicine, Helwan University, Egypt. | ||
| Abstract | ||
| The application of the anticancer antibiotic doxorubicin (Dox) has been limited due to the emergence of toxicities affecting vital organs, including the kidneys. The anti-trypanosomal drug diminazene aceturate (DIZE) was found to activate ACE2 and have multiple protective advantages. This study sought to elucidate the probable mechanisms and renoprotective benefits of DIZE in DOX-induced nephrotoxicity. Thirty male albino rats were divided into three groups: DOX, DOX+DIZE, and control groups, with ten rats in each category. After 8 weeks serum urea, serum creatinine, urine albumin, creatinine clearance, renal angiotensin II, renal angiotensin-converting enzyme 2, renal malondialdehyde, renal superoxide dismutase, renal tumor necrosis factor-alpha, renal interleukin-6, and renal gene expression of nuclear factor kappa B and Toll-like receptor 4 were assessed. Supplementary assessments of NF-kB and TLR4 immunoreactivity in the kidney were conducted. In the DOX group, serum levels of urea and creatinine, along with urinary albumin, renal MDA, renal TNF-α, renal IL-6, renal Ang II, and the renal gene expression and immune-reactivity of TLR4 and NF-κB, were significantly elevated compared to the control group; conversely, renal SOD, creatinine clearance, and renal ACE2 values in the DOX group were markedly diminished relative to the control. DIZE significantly improved the alterations caused by DOX-induced nephrotoxicity. DIZE affords renoprotection in DOX rats by downregulating the renal TLR4–NF-kB pathway and acting as an ACE2 activator, hence modifying the kidneys' anti-inflammatory and antioxidant properties | ||
| Keywords | ||
| ACE2 Diminazene; Doxorubicin NF-kB; Nephrotoxicity; TLR4 | ||
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