Xiao Li1, Ting Zhang2, Jian Geng3, Zhuguo Wu4, Liting Xu2, Jixing Liu2, Jianwei Tian2, Zhanmei Zhou2, Jing Nie2, Xiaoyan Bai2. 1. 1Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China. 2. 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. 3. 3Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China. 4. 4Department of Internal Medicine, the Second Clinical Medical College, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.
Abstract
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-β-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 β-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/β-catenin activation, providing new evidence for understanding the role of lipid accumulation in DN.
Aims: Diabetic nephropathy (DN) is the principal cause of mortality and morbidity in diabeticpatients, 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 diabeticmice 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-β-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 β-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/β-catenin activation, providing new evidence for understanding the role of lipid accumulation in DN.