Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Int Immunopharmacol. 2024 Jan 5;126:111179. doi: 10.1016/j.intimp.2023.111179. Epub 2023 Nov 22.
Nephrotoxicity is a serious complication commonly encountered with gentamicin (GTM) treatment. Permeabilization of lysosomes with subsequent cytoplasmic release of GTM and cathepsins is considered a crucial issue in progression of GTM toxicity. This study was designed to evaluate the prospective defensive effect of lysosomal membrane stabilization by imipramine (IMP) against GTM nephrotoxicity in rats. GTM (30 mg/kg/h) was intraperitoneally administered over 4 h daily (120 mg/kg/day) for 7 days. IMP (30 mg/kg/day) was orally administered for 14 days; starting 7 days before and then concurrently with GTM. On 15th day, samples (urine, blood, kidney) were collected to estimate biomarkers of kidney function, lysosomal stability, apoptosis, and inflammation. IMP administration to GTM-treated rats ameliorated the disruption in lysosomal membrane stability induced by GTM. That was evidenced by enhanced renal protein expressions of LAMP2 and PI3K, but reduced cathepsin D cytoplasmic expression in kidney sections. Besides, IMP guarded against apoptosis in GTM-treated rats by down-regulation of the pro-apoptotic (tBid, Bax, cytochrome c) and the effector cleaved caspase-3 expressions, while the anti-apoptotic Bcl-2 expression was enhanced. Additionally, the inflammatory cascade p38 MAPK/NF-κB/TNF-α was attenuated in GTM + IMP group along with marked improvement in kidney function biomarkers, compared to GTM group. These findings were supported by the obvious improvement in histological architecture. Furthermore, in vitro enhancement of the antibacterial activity of GTM by IMP confers an additional benefit to their combination. Conclusively, lysosomal membrane stabilization by IMP with subsequent suppression of tBid/cytochrome c/cleaved caspase-3 apoptotic signaling could be a promising protective strategy against GTM nephrotoxicity.
肾毒性是庆大霉素（GTM）治疗中常见的严重并发症。溶酶体的通透性及其随后的细胞质释放 GTM 和组织蛋白酶被认为是 GTM 毒性进展的关键问题。本研究旨在评估用丙咪嗪（IMP）稳定溶酶体膜对大鼠 GTM 肾毒性的潜在防御作用。GTM（30mg/kg/h）每天腹膜内给药 4 小时（120mg/kg/天），共 7 天。IMP（30mg/kg/天）口服给药 14 天；从 GTM 前 7 天开始，并与 GTM 同时给药。第 15 天，收集尿液、血液和肾脏样本，以评估肾功能、溶酶体稳定性、细胞凋亡和炎症的生物标志物。IMP 给药可改善 GTM 引起的溶酶体膜稳定性破坏。这表现在肾脏组织切片中 LAMP2 和 PI3K 蛋白表达增加，而组织蛋白酶 D 细胞质表达减少。此外，IMP 通过下调促凋亡（tBid、Bax、细胞色素 c）和效应半胱天冬酶-3 表达来保护 GTM 处理的大鼠免于细胞凋亡，同时增强抗凋亡 Bcl-2 表达。此外，与 GTM 组相比，GTM+IMP 组的 p38 MAPK/NF-κB/TNF-α 炎症级联反应减弱，肾功能生物标志物明显改善。这些发现得到了组织学结构明显改善的支持。此外，IMP 增强 GTM 的抗菌活性为它们的联合应用提供了额外的益处。总之，IMP 稳定溶酶体膜，随后抑制 tBid/细胞色素 c/半胱天冬酶-3 凋亡信号，可能是一种有前途的防治 GTM 肾毒性的保护策略。
