Advanced Oxidation Protein Products Promote Lipotoxicity and Tubulointerstitial Fibrosis via CD36/β-Catenin Pathway in Diabetic Nephropathy
Advanced Oxidation Protein Products Promote Lipotoxicity and Tubulointerstitial Fibrosis via CD36/β-Catenin Pathway in Diabetic Nephropathy
复制标题
高级氧化蛋白产品通过 CD36/β-连环蛋白途径促进糖尿病肾病的脂毒性和肾小管间质纤维化
DOI：
10.1089/ars.2018.7634
复制
发表时间：
2019-09-01
影响因子：
6.6
通讯作者：
Bai, Xiaoyan
中科院分区：
文献类型：
--
作者：
Li, Xiao;Zhang, Ting;Bai, Xiaoyan
目标：糖尿病肾病（DN）是糖尿病患者死亡和发病的主要原因，其进展与肾小管间质纤维化（TIF）密切相关。晚期氧化蛋白产物（AOPP）在慢性肾功能衰竭患者中已被检测到，导致近端肾小管上皮细胞损伤。CD 36是AOPP的已知受体，是脂质稳态的重要调节剂，易导致肾小管损伤。然而，AOPP是否通过CD 36受体途径诱导脂毒性仍然未知。在此，我们测试了AOPP在糖尿病中积累引起脂毒性的假设，通过CD 36信号通路引起肾TIF。结果如下：在DN患者和糖尿病小鼠体内，AOPP超负荷诱导脂肪生成（CD 36和固醇调节元件结合蛋白1上调）、纤维化（纤连蛋白上调）和肾功能下降（血清肌酐和N-乙酰-β-d-氨基葡萄糖苷酶升高，估计肾小球滤过率降低）。在体外HK-2细胞中，高糖通过CD 36受体途径刺激AOPP诱导的脂毒性、凋亡和纤维化。此外，夹竹桃麻素消除AOPP诱导的脂质积累和CD 36抑制显着减轻AOPP诱导的线粒体损伤，脂毒性和肾纤维化。此外，我们提供了AOPPs过载诱导β-连环蛋白结合CD 36启动子区域富集的机制证据。创新与结论：我们的数据揭示了AOPP通过CD 36依赖性Wnt/β-catenin激活在触发脂毒性和纤维化中的主要作用，为理解脂质积聚在DN中的作用提供了新的证据。
Aims: Diabetic nephropathy (DN) is the principal cause of mortality and morbidity in diabetic patients, the progression of which correlates best with tubulointerstitial fibrosis (TIF). Advanced oxidation protein products (AOPPs) have been detected in patients with chronic renal failure, causing injuries to proximal tubular epithelial cells. CD36, a known receptor for AOPP, is an important modulator of lipid homeostasis, predisposing to renal tubular damage. However, whether AOPPs induce lipotoxicity via the CD36 receptor pathway remains unknown. Herein, we tested the hypothesis that AOPPs accumulation in diabetes incurs lipotoxicity, causing renal TIF via the CD36 signaling pathway. Results: In DN patients and diabetic mice in vivo, AOPPs overload induces lipogenesis (upregulation of CD36 and sterol regulatory element-binding protein 1), fibrosis (upregulation of Fibronectin), and renal function decline (increased serum creatinine and N-acetyl-beta-d-glucosaminidase, decreased estimated glomerular filtration rate). In HK-2 cells in vitro, high glucose stimulated AOPPs-induced lipotoxicity, apoptosis, and fibrosis via the CD36 receptor pathway. In addition, apocynin abrogated AOPPs-induced lipid accumulation and CD36 inhibition significantly mitigated AOPPs-induced mitochondrial injuries, lipotoxicity, and renal fibrosis. Further, we provide mechanistic evidence that AOPPs overload induces the enrichment of beta-catenin binding the CD36 promoter region. Innovation and Conclusion: Our data reveal a major role of AOPPs in triggering lipotoxicity and fibrosis via CD36-dependent Wnt/beta-catenin activation, providing new evidence for understanding the role of lipid accumulation in DN.