Abd El-Baset Samia A, Mazen Nehad F, Abdul-Maksoud Rehab S, Kattaia Asmaa A A
Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig Egypt.
Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig Egypt.
Tissue Barriers. 2023 Jan 2;11(1):2069966. doi: 10.1080/21688370.2022.2069966. Epub 2022 May 3.
Diabetic nephropathy (DN) is the most frequent cause of end-stage renal failure. Zinc oxide nanoparticles (ZnO-NPs) are promising antidiabetic agents. Our aim was to evaluate the prospective efficacy of ZnO-NPs in treating DN in streptozotocin-induced diabetic rats. Rats were randomly dispersed into three sets: control group, DN group and DN + ZnO-NPs group. ZnO-NPs were given at a dose of 10 mg/kg/day by oral gavage for 4 weeks. Urine and blood samples were processed for biochemical analyses. Kidney samples were managed for light and electron microscopy studies. Immune histochemical staining of P53, aquaporin11 (AQP11) and mechanistic target of rapamycin (mTOR) were performed. Gene analyses of nephrin, podocin, beclin-1, LC3 and p62 were done. Administration of ZnO-NPs ameliorated the functional and histopathological alterations of the kidney in a rat model of diabetic nephropathy. ZnO-NPs retained the constancy of the glomerular filtration barrier and restored almost normal renal structure. This was confirmed by upregulation of mRNA expression of podocyte markers (nephrin and podocin) and AQP11 immune histochemical expression in the renal tubules. The beneficial outcomes of ZnO-NPs might be attributed to activation of autophagy through inhibiting mTOR signaling pathway. ZnO-NPs enhanced beclin-1 and LC3 mRNA expressions and reduced p62 mRNA expression. ZnO-NPs also exerted anti-apoptotic potential (evidenced by the decrease in p53 immune expression), anti-inflammatory and anti-oxidant effect [endorsed by suppression of serum cyclooxygenase-2 (COX-2) enzyme activity, tissue nuclear factor kappa beta (NF-κB) level and blood hypoxia-inducible factors (HIF-1α) level]. These results may point the way to an effective therapy of DN.Abbreviations: AQP11 Aquaporin11; BUN: Blood urea nitrogen; COX-2: Cyclooxygenase-2; DAB: 3, 3'-diaminobenzidine; DM: Diabetes mellitus; DN: Diabetic nephropathy; ELISA: Enzyme-linked immunosorbent assay; H&E: Hematoxylin & eosin; HIF-1α: Hypoxia-inducible factors; iNOS: inducible nitric oxide synthase; LC3: Microtubule-associated protein 1 light chain 3; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa beta; NPs: Nanoparticles; PAS: Periodic acid Schiff; PCR: Polymerase chain reaction; PGE2: Prostaglandin E2; ROS: Reactive oxygen species; STZ: Streptozotocin; X ± SEM: Mean ± standard error of means; Zn: Zinc; ZnO-NPs: Zinc oxide nanoparticles.
糖尿病肾病（DN）是终末期肾衰竭最常见的病因。氧化锌纳米颗粒（ZnO-NPs）是很有前景的抗糖尿病药物。我们的目的是评估ZnO-NPs对链脲佐菌素诱导的糖尿病大鼠DN的潜在治疗效果。大鼠被随机分为三组：对照组、DN组和DN + ZnO-NPs组。通过口服灌胃给予ZnO-NPs，剂量为10 mg/kg/天，持续4周。对尿液和血液样本进行生化分析。对肾脏样本进行光镜和电镜研究。进行P53、水通道蛋白11（AQP11）和雷帕霉素作用靶点（mTOR）的免疫组织化学染色。对nephrin、podocin、beclin-1、LC3和p62进行基因分析。给予ZnO-NPs改善了糖尿病肾病大鼠模型肾脏的功能和组织病理学改变。ZnO-NPs维持了肾小球滤过屏障的稳定性，并使肾脏结构恢复到几乎正常。这通过足细胞标志物（nephrin和podocin）mRNA表达上调以及肾小管中AQP11免疫组织化学表达得以证实。ZnO-NPs的有益效果可能归因于通过抑制mTOR信号通路激活自噬。ZnO-NPs增强了beclin-1和LC3 mRNA表达并降低了p62 mRNA表达。ZnO-NPs还发挥了抗凋亡潜力（p53免疫表达降低证明）、抗炎和抗氧化作用[血清环氧化酶-2（COX-2）酶活性、组织核因子κB（NF-κB）水平和血液缺氧诱导因子（HIF-1α）水平受到抑制证实]。这些结果可能为DN的有效治疗指明方向。
AQP11水通道蛋白11；BUN：血尿素氮；COX-2：环氧化酶-2；DAB：3,3'-二氨基联苯胺；DM：糖尿病；DN：糖尿病肾病；ELISA：酶联免疫吸附测定；H&E：苏木精和伊红；HIF-1α：缺氧诱导因子；iNOS：诱导型一氧化氮合酶；LC3：微管相关蛋白1轻链3；mTOR：雷帕霉素作用靶点；NF-κB：核因子κB；NPs：纳米颗粒；PAS：过碘酸希夫；PCR：聚合酶链反应；PGE2：前列腺素E2；ROS：活性氧；STZ：链脲佐菌素；X±SEM：平均值±均值标准误；Zn：锌；ZnO-NPs：氧化锌纳米颗粒
