Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Department of Histology and cell biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Fundam Clin Pharmacol. 2022 Apr;36(2):324-337. doi: 10.1111/fcp.12736. Epub 2021 Nov 11.
Management of diabetic nephropathy (DN) is far from satisfactory. There is a rising role of the involvement of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway in the pathogenesis of DN. This study aimed at investigating the renoprotective effects of PI3K/AKT pathway via sitagliptin in a rat model of DN. Thirty-two male Wistar rats were divided into four groups (eight rats each): (I) control, (II) sitagliptin, (III) DN, and (IV) DN + sitagliptin. Fasting blood glucose (FBG), kidney index, and kidney function tests in both blood and urine were measured. The levels of superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) and gene expressions of PI3K, pPI3K, AKT, and pAKT in renal tissue were detected. Renal histopathological and immunohistochemical studies were evaluated. DN + sitagliptin group showed significant decrease in FBG and kidney index, improvement in kidney function tests, and a decrease in levels of TNF-α and TGF-β in renal tissues compared with DN group. This was associated with significant increase in SOD and gene expressions of PI3K and AKT and their phosphorylated active forms in renal tissue in DN + sitagliptin group compared with DN group. Moreover, DN + sitagliptin group showed apparent decrease in amount of collagen fibers and expression of alpha-smooth muscle actin (α-SMA) compared with DN group. This work shows that sitagliptin improved renal functions and histopathological changes, impeded inflammation, and oxidative stress and upregulated PI3K/AKT pathway which highlights its renoprotective effects in a rat model of DN.
糖尿病肾病（DN）的管理远未令人满意。越来越多的证据表明，磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）通路参与了 DN 的发病机制。本研究旨在通过西他列汀研究 PI3K/AKT 通路在糖尿病肾病大鼠模型中的肾保护作用。32 只雄性 Wistar 大鼠分为四组（每组 8 只）：（I）对照组、（II）西他列汀组、（III）DN 组和（IV）DN+西他列汀组。测量空腹血糖（FBG）、肾脏指数以及血液和尿液中的肾功能测试。检测肾组织中超氧化物歧化酶（SOD）、肿瘤坏死因子-α（TNF-α）和转化生长因子-β（TGF-β）的水平以及 PI3K、pPI3K、AKT 和 pAKT 的基因表达。评估肾组织的病理组织学和免疫组织化学研究。与 DN 组相比，DN+西他列汀组的 FBG 和肾脏指数显著降低，肾功能测试改善，肾组织中 TNF-α和 TGF-β水平降低。这与 DN+西他列汀组肾组织中 SOD 以及 PI3K 和 AKT 的基因表达及其磷酸化活性形式的显著增加有关。此外，与 DN 组相比，DN+西他列汀组胶原纤维含量和α-平滑肌肌动蛋白（α-SMA）表达明显减少。这项工作表明，西他列汀改善了肾功能和组织病理学变化，抑制了炎症和氧化应激，并上调了 PI3K/AKT 通路，这突出了其在糖尿病肾病大鼠模型中的肾保护作用。
