Activation of angiotensin-converting enzyme 2 mitigates Doxorubicin induced nephrotoxicity by TLR4/NF-kB downregulation

Khodir, Suzan A; Abdelrahman, Sara Elsayed; Abd El-aziz, noha; Aboul-Ela, Yasmin M; Khedr, Sara A; El-Sawaf, Eman A; Abd EL-Khalek, Soha H; El Menyawi, Menna Allah I; Yusuf, Walaa Ahmed; Greash, Mohamed Ahmed; Shawky, Noha O

doi:10.21608/mjfmct.2025.353763.1095

	Activation of angiotensin-converting enzyme 2 mitigates Doxorubicin induced nephrotoxicity by TLR4/NF-kB downregulation
Mansoura Journal of Forensic Medicine and Clinical Toxicology
Volume 33, Issue 2, July 2025, Page 1-11 PDF (986.61 K)
Document Type: Original Article
DOI: 10.21608/mjfmct.2025.353763.1095
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Authors
Suzan A Khodir ¹; Sara Elsayed Abdelrahman²; noha Abd El-aziz³; Yasmin M Aboul-Ela⁴; Sara A Khedr⁵; Eman A El-Sawaf ⁶; 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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