香芹酚通过调节 TGF-β1/Smad 信号传导和炎症来保持抗氧化状态并减轻肾纤维化,Food & Function

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香芹酚通过调节 TGF-β1/Smad 信号传导和炎症来保持抗氧化状态并减轻肾纤维化
Food & Function ( IF 5.1 ) Pub Date : 2022-09-20 , DOI: 10.1039/d2fo01384c
Chetan Ram ₁ , Shobhit Gairola ₁ , Abu Mohammad Syed ₁ , Shobhit Verma ₂ , Madhav Nilakanth Mugale ₂ , Bidya Dhar Sahu ₁

Affiliation

具有多种病因的慢性肾病 (CKD) 正在成为一种与炎症和间质纤维化相关的具有挑战性的肾脏疾病。香芹酚 (CVL) 是一种生物活性单萜类化合物，在牛至、百里香和佛手柑中大量发现，具有多种药理作用。然而，CVL 对肾脏纤维化变化的影响尚不明确。在目前的研究中，通过单侧输尿管阻塞 (UUO) 诱导的肾纤维化的稳健小鼠模型用于研究 CVL 的抗纤维化活性。用两种不同的口服剂量 CVL（25 mg kg ^-1和 50 mg kg ^-1体重）连续 14 天。UUO 诱导导致肾功能受损、严重的组织学损伤和阻塞肾脏中的胶原沉积。我们的研究结果揭示了转化生长因子-β1 (TGF-β1) 和 NF-κB (p65) 信号的深度激活以及抗氧化蛋白、核因子-红细胞因子 2 相关因子 2 (Nrf2)、NAD(P) 的下调H：阻塞肾脏中的醌氧化还原酶 1 (NQO1) 和超氧化物歧化酶 (SOD)。CVL 给药显着恢复了抗氧化蛋白和肾脏组织学变化。此外，与 UUO 相比，CVL 减弱了 NF-κB (p65) 磷酸化并降低了肿瘤坏死因子 (TNF)-α、白细胞介素 (IL)-1β、IL-6 和环氧合酶 2 (COX-2) 的水平控制组。CVL 还减轻了 TGF-β1 纤维化蛋白水平的升高，pSmad2/3、胶原蛋白 I、胶原蛋白 III、纤连蛋白和肌成纤维细胞活化和上皮间质转化 (EMT) 标志物，包括肾脏中的 α-平滑肌肌动蛋白 (α-SMA)、E-钙粘蛋白和波形蛋白。调查结果来自体外研究还证实，CVL 抑制 TGF-β1 刺激的肾小管上皮细胞（NRK 52E 细胞）的 EMT 过程。总的来说，我们的研究结果表明，CVL 给药通过靶向氧化应激和炎症来减轻肾纤维化。

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Carvacrol preserves antioxidant status and attenuates kidney fibrosis via modulation of TGF-β1/Smad signaling and inflammation

Chronic kidney disease (CKD) with diverse aetiologies is emerging as a challenging kidney disorder associated with inflammation and interstitial fibrosis. Carvacrol (CVL) is a bioactive monoterpenoid found abundantly in oregano, thyme, and bergamot, having diverse pharmacological benefits. However, the effect of CVL against fibrotic changes in the kidneys is poorly defined. In the current study, a robust mouse model of renal fibrosis induced through unilateral ureteral obstruction (UUO) is used to investigate the anti-fibrotic activity of CVL. The mice were treated with two different oral doses of CVL (25 mg kg⁻¹ and 50 mg kg⁻¹ body weight) for 14 consecutive days. The UUO induction resulted in impaired renal function, severe histological damage, and collagen deposition in the obstructed kidney. Our findings revealed profound activation of transforming growth factor-β1 (TGF-β1) and NF-κB (p65) signaling along with the downregulation of antioxidant proteins, nuclear factor-erythroid factor 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD) in the obstructed kidney. CVL administration markedly recovered antioxidant proteins and kidney histological changes. In addition, CVL blunted the NF-κB (p65) phosphorylation and reduced the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and cyclooxygenase 2 (COX-2) compared to the UUO control group. CVL also alleviated the increased fibrotic protein levels of TGF-β1, pSmad2/3, collagen I, collagen III, fibronectin, and myofibroblast activation and epithelial–mesenchymal transition (EMT) markers, including alpha-smooth muscle actin (α-SMA), E-cadherin, and vimentin in the kidneys. Findings from in vitro study also confirmed that CVL inhibits the EMT process in TGF-β1 stimulated renal tubular epithelial cells (NRK 52E cells). Collectively, our findings indicate that CVL administration attenuates kidney fibrosis by targeting oxidative stress and inflammation.

更新日期：2022-09-20

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