Lee Wen-Jane, Liu Shing-Hwa, Chiang Chih-Kang, Lin Shih-Yi, Liang Kae-Woei, Chen Cheng-Hsu, Tien Hsing-Ru, Chen Pei-Hsuan, Wu Jen-Pey, Tsai Yi-Ching, Lai De-Wei, Chang Yi-Chieh, Sheu Wayne Huey-Herng, Sheu Meei-Ling
1 Department of Medical Research, Taichung Veterans General Hospital , Taichung, Taiwan .
2 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .
Antioxid Redox Signal. 2016 Feb 1;24(4):217-231. doi: 10.1089/ars.2015.6310. Epub 2015 Nov 16.
Activation of glomerular mesangial cells (MCs) and functional changes of renal tubular cells are due to metabolic abnormalities, oxidative stress, and matrix accumulation in the diabetic nephropathy (DN). Aryl hydrocarbon receptor (AhR) activation has been implicated in DN. In this study, we investigated the role of AhR in the pathophysiological processes of DN using AhR knockout (AhRKO) and pharmacological inhibitor α-naphthoflavone mouse models.
The increased blood glucose, glucose intolerance, MC activation, macrophage infiltration, and extracellular matrix (ECM) accumulation were significantly attenuated in AhRKO mice with diabetic inducer streptozotocin (STZ) treatment. AhR deficiency by genetic knockout or pharmacological inhibition also decreased the induction of cyclooxygenase-2 (COX-2)/prostaglandin E (PGE), lipid peroxidation, oxidative stress, NADPH oxidase activity, and N-ɛ-carboxymethyllysine (CML, a major advanced glycation end product) in STZ-induced diabetic mice. CML showed remarkably increased AhR/COX-2 DNA-binding activity, protein-DNA interactions, gene regulation, and ECM formation in MCs and renal proximal tubular cells, which could be reversed by siRNA-AhR transfection. CML-increased AhR nuclear translocation and biological activity in MCs and renal proximal tubular cells could also be effectively attenuated by antioxidants.
We elucidate for the first time that AhR plays an important role in MC activation, macrophage infiltration, and ECM accumulation in DN conferred by oxidative stress.
AhR-regulated COX-2/PGE expression and ECM deposition through oxidative stress cascade is involved in the CML-triggered MC activation and macrophage infiltration. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic microvascular complications. Antioxid. Redox Signal. 24, 217-231.
在糖尿病肾病（DN）中，肾小球系膜细胞（MCs）的激活和肾小管细胞的功能变化是由代谢异常、氧化应激和基质蓄积引起的。芳烃受体（AhR）的激活与DN有关。在本研究中，我们使用AhR基因敲除（AhRKO）和药理学抑制剂α-萘黄酮小鼠模型，研究了AhR在DN病理生理过程中的作用。
用糖尿病诱导剂链脲佐菌素（STZ）处理的AhRKO小鼠中，血糖升高、葡萄糖不耐受、MC激活、巨噬细胞浸润和细胞外基质（ECM）蓄积均显著减轻。通过基因敲除或药理学抑制使AhR缺乏，也降低了STZ诱导的糖尿病小鼠中环氧合酶-2（COX-2）/前列腺素E（PGE）的诱导、脂质过氧化、氧化应激、NADPH氧化酶活性以及N-ε-羧甲基赖氨酸（CML，一种主要的晚期糖基化终产物）。CML在MCs和肾近端小管细胞中显著增加AhR/COX-2 DNA结合活性、蛋白质-DNA相互作用、基因调控和ECM形成，而这可通过siRNA-AhR转染逆转。抗氧化剂也可有效减轻CML增加的AhR在MCs和肾近端小管细胞中的核转位和生物学活性。
我们首次阐明AhR在氧化应激所致的DN的MC激活、巨噬细胞浸润和ECM蓄积中起重要作用。
AhR通过氧化应激级联反应调节COX-2/PGE表达和ECM沉积，参与CML触发的MC激活和巨噬细胞浸润。这些发现为减少糖尿病微血管并发症的治疗方法的开发提供了新见解。《抗氧化与氧化还原信号》24卷，217 - 231页。
