Al-Maskari Raya, Abdelrahman Aly M, Ali Haytham, Manoj Priyadarsini, Al Suleimani Yousuf
Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman.
Department of Animal and Veterinary Sciences, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat 123, Oman.
Toxicol Rep. 2024 Nov 6;13:101800. doi: 10.1016/j.toxrep.2024.101800. eCollection 2024 Dec.
This study aimed to investigate the potential protective effects of riociguat, a soluble guanylyl cyclase (sGC) stimulator, on kidney function and structure in rats with acute kidney injury (AKI) induced by the chemotherapeutic drug doxorubicin (DX). Rats were subjected to a single intraperitoneal injection of DX (13.5 mg/kg) on the 5th day, either alone or in combination with low-dose riociguat (3 mg/kg/day), or high-dose riociguat (10 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Kidney tissues were examined histopathologically. DX-induced nephrotoxicity was characterized by increased plasma urea, creatinine, uric acid and neutrophil gelatinase-associated lipocalin (NGAL). DX also decreased creatinine clearance and albumin levels and increased urinary N-acetyl-β-D-glucosaminidase (NAG) activity. Furthermore, DX increased the inflammatory markers interleukin 1 beta (IL-1 β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). DX further induced oxidative stress injury evidenced by decreased glutathione reductase (GR) activity, total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase levels and increased malondialdehyde (MDA) levels. Concomitant treatment with riociguat ameliorated these DX-induced changes with parallel histopathological improvements but the effects were more favorable with high-dose riociguat. The observed renoprotective effects of riociguat can be partly attributed to the anti-inflammatory and anti-oxidant properties of this drug.
本研究旨在探讨可溶鸟苷酸环化酶（sGC）刺激剂利奥西呱对多柔比星（DX）诱导的急性肾损伤（AKI）大鼠肾功能和结构的潜在保护作用。在第5天，大鼠接受单次腹腔注射DX（13.5 mg/kg），单独注射或与低剂量利奥西呱（3 mg/kg/天）或高剂量利奥西呱（10 mg/kg/天）联合注射，连续8天。检测血浆和尿液中与肾功能、氧化应激和炎症相关的各种标志物。对肾组织进行组织病理学检查。DX诱导的肾毒性表现为血浆尿素、肌酐、尿酸和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）升高。DX还降低了肌酐清除率和白蛋白水平，并增加了尿N-乙酰-β-D-氨基葡萄糖苷酶（NAG）活性。此外，DX增加了炎症标志物白细胞介素1β（IL-1β）、白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-α）。DX进一步诱导氧化应激损伤，表现为谷胱甘肽还原酶（GR）活性、总抗氧化能力（TAC）、超氧化物歧化酶（SOD）和过氧化氢酶水平降低，丙二醛（MDA）水平升高。利奥西呱联合治疗改善了这些DX诱导的变化，并伴有组织病理学改善，但高剂量利奥西呱的效果更显著。观察到的利奥西呱的肾脏保护作用部分可归因于该药物的抗炎和抗氧化特性。
