1Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
Antioxid Redox Signal. 2019 Sep 1;31(7):521-538. doi: 10.1089/ars.2018.7634.
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 the CD36 receptor pathway remains unknown. Herein, we tested the hypothesis that AOPPs accumulation in diabetes incurs lipotoxicity, causing renal TIF the CD36 signaling pathway. In DN patients and diabetic mice , 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-β-d-glucosaminidase, decreased estimated glomerular filtration rate). In HK-2 cells , high glucose stimulated AOPPs-induced lipotoxicity, apoptosis, and fibrosis 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 β-catenin binding the CD36 promoter region. Our data reveal a major role of AOPPs in triggering lipotoxicity and fibrosis CD36-dependent Wnt/β-catenin activation, providing new evidence for understanding the role of lipid accumulation in DN.
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）相关性最佳。在慢性肾衰竭患者中已经检测到晚期氧化蛋白产物（AOPPs），导致近端肾小管上皮细胞损伤。CD36，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，AOPPs 是否引起脂毒性，CD36 受体途径尚不清楚。在此，我们检验了一个假设，即在糖尿病中 AOPPs 的积累会引起脂毒性，导致肾脏 TIF 和 CD36 信号通路。在 DN 患者和糖尿病小鼠中，AOPPs 过载会诱导脂肪生成（CD36 和固醇调节元件结合蛋白 1 的上调）、纤维化（纤连蛋白的上调）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，肾小球滤过率估计值降低）。在 HK-2 细胞中，高葡萄糖刺激 AOPPs 诱导的脂毒性、细胞凋亡和纤维化 CD36 受体途径。此外，阿朴肉桂酸酯可阻断 AOPPs 诱导的脂质积累，CD36 抑制可显著减轻 AOPPs 诱导的线粒体损伤、脂毒性和肾脏纤维化。此外，我们提供了机制证据，表明 AOPPs 过载诱导β-catenin 与 CD36 启动子区域结合的富集。我们的数据揭示了 AOPPs 在触发脂毒性和纤维化中的主要作用，这与 CD36 依赖性 Wnt/β-catenin 激活有关，为理解脂质积累在 DN 中的作用提供了新的证据。
