Yao Fang, Li Zhen, Ehara Takashi, Yang Lin, Wang Dandan, Feng Lulu, Zhang Yiming, Wang Kun, Shi Yonghong, Duan Huijun, Zhang Lianshan
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Pathology, the First Hospital of Changsha City, Changsha, China.
Mol Cell Endocrinol. 2015 Aug 15;411:232-42. doi: 10.1016/j.mce.2015.05.003. Epub 2015 May 6.
Type 2 diabetes is characterized by hyperglycemia and deregulated lipid metabolism with increased plasma non-esterified fatty acids (NEFA). Apoptosis of glomerular cells is a hallmark in diabetic glomerulosclerosis. Fatty acid-binding protein 4 (FABP4), a carrier protein for fatty acids, has been linked to diabetes and diabetic nephropathy (DN). Here we aimed to investigate the link between FABP4 and apoptosis in diabetic glomerulosclerosis. We first evaluated the presence of FABP4 and ER stress markers as well as apoptosis-related proteins in renal biopsies of patients with DN. Then we used FABP4 inhibitor BMS309403 or siRNA to further investigate the role of FABP4 in ER stress and apoptosis induced by NEFA or high glucose in cultured human mesangial cells (HMCs). We found FABP4 was expressed mainly in glomerular mesangial cells of the human renal biopsies and the glomerular FABP4 was increased in renal biopsies of DN. The up-regulation of FABP4 was accompanied with increased glucose-regulated protein 78 (GRP78) and Caspase-12 as well as down-regulated B-cell CLL/lymphoma 2 (Bcl-2) in glomeruli. Along with the induction of FABP4 and apoptosis, GRP78 and its three sensors as well as C/EBP homologous protein (CHOP) and Caspase-12 were induced in HMCs treated with NEFA or high glucose and these responses were attenuated or even abrogated by treating with FABP4 inhibitor or FABP4 siRNA. Ultrastructure observation confirmed the lipotoxicity of oleic acid by showing the morphological damage in HMCs. Our data suggest that FABP4 in glomerular mesangial cells is up-regulated in DN and FABP4 mediates apoptosis via the ER stress in HMCs.
2型糖尿病的特征是高血糖和脂质代谢失调，血浆非酯化脂肪酸（NEFA）增加。肾小球细胞凋亡是糖尿病肾小球硬化的一个标志。脂肪酸结合蛋白4（FABP4）是一种脂肪酸载体蛋白，与糖尿病和糖尿病肾病（DN）有关。在这里，我们旨在研究FABP4与糖尿病肾小球硬化中细胞凋亡之间的联系。我们首先评估了DN患者肾活检中FABP4、内质网应激标志物以及凋亡相关蛋白的存在情况。然后我们使用FABP4抑制剂BMS309403或小干扰RNA（siRNA）进一步研究FABP4在培养的人系膜细胞（HMCs）中由NEFA或高糖诱导的内质网应激和细胞凋亡中的作用。我们发现FABP4主要在人肾活检的肾小球系膜细胞中表达，并且在DN患者的肾活检中肾小球FABP4增加。FABP4的上调伴随着肾小球中葡萄糖调节蛋白78（GRP78）和半胱天冬酶-12的增加以及B细胞淋巴瘤/白血病-2（Bcl-2）的下调。随着FABP4和细胞凋亡的诱导，在用NEFA或高糖处理的HMCs中，GRP78及其三个感受器以及C/EBP同源蛋白（CHOP）和半胱天冬酶-12被诱导，并且这些反应在用FABP4抑制剂或FABP4 siRNA处理后减弱甚至消除。超微结构观察通过显示HMCs中的形态损伤证实了油酸的脂毒性。我们的数据表明，在DN中肾小球系膜细胞中的FABP4上调，并且FABP4通过HMCs中的内质网应激介导细胞凋亡。
