Mahmoud Nevertyty M, Elshazly Shimaa M, Hassan Arwa A, Soliman Eman
Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Int Immunopharmacol. 2023 Feb;115:109646. doi: 10.1016/j.intimp.2022.109646. Epub 2022 Dec 30.
Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Agomelatine, a melatonin receptor agonist, has a potent anti-inflammatory activity. The current study aimed to determine the ameliorative anti-inflammatory effect of agomelatine against DN.
We used 10 % fructose with streptozotocin (STZ) to induce DN in male Wistar rats. Diabetic rats were treated with agomelatine in presence or absence of melatonin receptor antagonist (luzindole) or Sirtuin1 (SIRT1) inhibitor (EX527). SIRT1 expression was measured by qRT-PCR and immunohistochemical analysis. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), 5'adenosine monophosphate-activated protein kinase (AMPK), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA. Histological assessment was performed using hematoxylin and eosin-stained renal sections.
Fructose and STZ treatment induced diabetes, insulin resistance, and renal damage accompanied by reduced SIRT1 expression, increased NFκB activation, and decreased AMPK phosphorylation in the kidney. Agomelatine treatment improved kidney histology and function and upregulated SIRT1 expression (2-fold). Inhibition of melatonin receptors and SIRT1 activity increased NFκB phosphorylation (2.13 and 1.98-folds, respectively), reduced AMPK activation (0.51 and 0.53-folds, respectively), increased inflammatory markers ICAM-1 (2.16 and 2.23-folds, respectively), VCAM-1 (2.19 and 2.26-folds, respectively), and MCP-1(2.84 and 3.12-folds, respectively), and inhibited the ameliorative effect of agomelatine on kidney structure and function.
Our findings reveal the ameliorative anti-inflammatory activity of agomelatine against STZ-induced DN and this effect is SIRT1- and melatonin receptor-dependent. Therefore, agomelatine may be beneficial to prevent the development of ESRD from diabetes mellitus.
糖尿病肾病（DN）是终末期肾病（ESRD）的主要病因。阿戈美拉汀是一种褪黑素受体激动剂，具有强大的抗炎活性。本研究旨在确定阿戈美拉汀对DN的改善抗炎作用。
我们用10%果糖联合链脲佐菌素（STZ）诱导雄性Wistar大鼠发生DN。糖尿病大鼠在有或无褪黑素受体拮抗剂（鲁辛朵）或沉默调节蛋白1（SIRT1）抑制剂（EX527）的情况下接受阿戈美拉汀治疗。通过qRT-PCR和免疫组织化学分析测定SIRT1表达。使用酶联免疫吸附测定法（ELISA）测量活化B细胞核因子κB（NFκB）、5'-腺苷单磷酸激活蛋白激酶（AMPK）、细胞间黏附分子-1（ICAM-1）、血管细胞黏附蛋白-1（VCAM-1）和单核细胞趋化蛋白-1（MCP-1）的表达。使用苏木精和伊红染色的肾脏切片进行组织学评估。
果糖和STZ治疗诱导了糖尿病、胰岛素抵抗和肾损伤，同时伴有肾脏中SIRT1表达降低、NFκB激活增加和AMPK磷酸化减少。阿戈美拉汀治疗改善了肾脏组织学和功能，并上调了SIRT1表达（2倍）。抑制褪黑素受体和SIRT1活性增加了NFκB磷酸化（分别为2.13倍和1.98倍），降低了AMPK激活（分别为0.51倍和0.53倍），增加了炎症标志物ICAM-1（分别为2.16倍和2.23倍）、VCAM-1（分别为2.19倍和2.26倍）和MCP-1（分别为2.84倍和3.12倍），并抑制了阿戈美拉汀对肾脏结构和功能的改善作用。
我们的研究结果揭示了阿戈美拉汀对STZ诱导的DN具有改善抗炎活性，且这种作用依赖于SIRT1和褪黑素受体。因此，阿戈美拉汀可能有助于预防糖尿病发展为ESRD。
