Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University.
Pharmacology Department, Egyptian Drug Authority (EDA), formerly known as National Organization for Drug Control and Research (NODCAR).
Biol Pharm Bull. 2024;47(5):1008-1020. doi: 10.1248/bpb.b23-00737.
The dipeptidyl peptidase-4 (DPP-4) inhibitors, a novel anti-diabetic medication family, are renoprotective in diabetes, but a comparable benefit in chronic non-diabetic kidney diseases is still under investigation. This study aimed to elucidate the molecular mechanisms of linagliptin's (Lina) protective role in a rat model of chronic kidney injury caused by tacrolimus (TAC) independent of blood glucose levels. Thirty-two adult male Sprague Dawley rats were equally randomized into four groups and treated daily for 28 d as follows: The control group; received olive oil (1 mL/kg/d, subcutaneously), group 2; received Lina (5 mg/kg/d, orally), group 3; received TAC (1.5 mg/kg/d, subcutaneously), group 4; received TAC plus Lina concomitantly in doses as the same previous groups. Blood and urine samples were collected to investigate renal function indices and tubular injury markers. Additionally, signaling molecules, epithelial-mesenchymal transition (EMT), and fibrotic-related proteins in kidney tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, immunohistochemical and histological examinations. Tacrolimus markedly induced renal injury and fibrosis as indicated by renal dysfunction, histological damage, and deposition of extracellular matrix (ECM) proteins. It also increased transforming growth factor β1 (TGF-β1), Smad4, p-extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P38/P38 mitogen-activated protein kinase (MAPK) protein levels. These alterations were markedly attenuated by the Lina administration. Moreover, Lina significantly inhibited EMT, evidenced by inhibiting Vimentin and α-smooth muscle actin (α-SMA) and elevating E-cadherin. Furthermore, Lina diminished hypoxia-related protein levels with a subsequent reduction in Snail and Twist expressions. We concluded that Lina may protect against TAC-induced interstitial fibrosis by modulating TGF-β1 mediated EMT via Smad-dependent and independent signaling pathways.
二肽基肽酶-4（DPP-4）抑制剂是一种新型的抗糖尿病药物家族，在糖尿病中具有肾脏保护作用，但在慢性非糖尿病肾脏疾病中的类似益处仍在研究中。本研究旨在阐明利拉利汀（Lina）在他克莫司（TAC）诱导的慢性肾损伤大鼠模型中的保护作用的分子机制，而不依赖于血糖水平。将 32 只成年雄性 Sprague Dawley 大鼠等分为四组，每天分别接受以下治疗 28 天：对照组；接受橄榄油（1ml/kg/d，皮下注射），第 2 组；接受 Lina（5mg/kg/d，口服），第 3 组；接受 TAC（1.5mg/kg/d，皮下注射），第 4 组；同时给予 TAC 和 Lina，剂量与前两组相同。收集血液和尿液样本以检测肾功能指标和肾小管损伤标志物。此外，通过酶联免疫吸附测定（ELISA）和 Western blot 分析、免疫组织化学和组织学检查评估肾脏组织中的信号分子、上皮-间充质转化（EMT）和纤维化相关蛋白。他克莫司明显诱导肾脏损伤和纤维化，表现为肾功能障碍、组织学损伤和细胞外基质（ECM）蛋白沉积。它还增加了转化生长因子β1（TGF-β1）、Smad4、p-细胞外信号调节激酶（ERK）1/2/ERK1/2 和 p-P38/P38 丝裂原激活蛋白激酶（MAPK）蛋白水平。这些变化在给予 Lina 后明显减弱。此外，Lina 通过抑制波形蛋白和α-平滑肌肌动蛋白（α-SMA）和升高 E-钙黏蛋白显著抑制 EMT。此外，Lina 降低缺氧相关蛋白水平，随后降低 Snail 和 Twist 的表达。我们得出结论，Lina 可能通过调节 TGF-β1 介导的 EMT 通过 Smad 依赖性和非依赖性信号通路来防止 TAC 诱导的间质纤维化。
