Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats

Yousuf Al Suleimani; Raya Al Maskari; Badreldin H Ali; Haytham Ali; Priyadarsini Manoj; Ali Al-Khamiyasi; Aly M Abdelrahman

doi:10.1016/j.toxrep.2023.11.005

Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats

Toxicol Rep. 2023 Nov 10:11:460-468. doi: 10.1016/j.toxrep.2023.11.005. eCollection 2023 Dec.

Authors

Yousuf Al Suleimani¹, Raya Al Maskari¹, Badreldin H Ali¹, Haytham Ali², Priyadarsini Manoj¹, Ali Al-Khamiyasi¹, Aly M Abdelrahman¹

Affiliations

¹ Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman.
² Department of Animal and Veterinary Sciences, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat 123, Oman.

Abstract

This study aimed to investigate the potential protective effects of diminazene, an activator of angiotensin II converting enzyme (ACE2), on kidney function and structure in rats with acute kidney injury (AKI) induced by the anticancer drug doxorubicin (DOX). The impact of diminazene was compared to that of two other drugs: the ACE inhibitor lisinopril and the angiotensin II type 1 (AT1) receptor blocker valsartan. Rats were subjected to a single intraperitoneal injection of DOX (13.5 mg/kg) on the 5th day, either alone or in combination with diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), or valsartan (30 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Additionally, kidney tissues were assessed histopathologically. DOX-induced nephrotoxicity was confirmed by elevated levels of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). DOX also led to increased urinary N-acetyl-β-D-glucosaminidase (NAG) activity and decreased creatinine clearance, albumin levels, and osmolality. Moreover, DOX caused a reduction in renal oxidative stress markers, including superoxide dismutase (SOD), glutathione reductase (GR), and catalase activities, while increasing malondialdehyde (MDA) levels. It also raised plasma inflammatory markers, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). Concurrently administering diminazene significantly mitigated these DOX-induced changes, including histopathological alterations like renal tubule necrosis, tubular casts, shrunken glomeruli, and increased renal fibrosis. Similar protective effects were observed with lisinopril and valsartan. These protective effects, at least in part, appear to result from the anti-inflammatory and antioxidant properties of these drugs. In summary, this study suggests that the administration of diminazene, lisinopril, or valsartan had comparable effects in ameliorating the biochemical and histopathological aspects of DOX-induced acute kidney injury in rats.

Keywords: ACE2 activator; Acute kidney injury; Diminazene; Doxorubicin; Lisinopril; Valsartan.