Junchao Liu1, Xia Gao1, Yihui Zhai1, Qian Shen1, Li Sun1, Chun Feng2, Jia Rao1, Haimei Liu1, Xiliang Zha3, Muyi Guo4, Duan Ma5, Zhigang Zhang4, Ruixi Li6, Hong Xu1. 1. Department of Nephrology and Rheumatology, Children's Hospital of Fudan University, Shanghai, China. 2. Institute of Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 3. Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai, China. 4. Department of Pathology and Key Laboratory of Molecular Medicine, Shanghai Medical College of Fudan University, Shanghai, China. 5. Institute of Biomedical Sciences, Fudan University, Shanghai, China. 6. Department of Anatomy, Histology and Embryology, Shanghai Medical College of Fudan University, Shanghai, China.
Abstract
BACKGROUND: Angiopoietin-like-3 (ANGPTL3) expression is increased in glomerular podocytes of nephrotic syndrome. We hypothesize whether ANGPTL3 plays an important role in podocyte injury and promoting proteinuria. METHODS: Angptl3(+/+) and Angptl3(-/-) female mice on B6;129S5 gene background were injected with adriamycin by tail vein at the dose of 25 mg/Kg to produce nephropathy. Proteinuira was measured and podocytes ultrastructure was observed by electron microscopy. The interaction between ANGPTL3 and intergrin β3 was analyzed by CO-IP and confocal immunofluorescence. The relative gene and protein expression were analyzed by RT-PCR and western blot. RESULTS: The deletion of ANGPTL3 tremendously attenuates proteinuria (more than a fivefold decrease in albuminuria) and protects podocytes from injury in a mouse model of adriamycin-induced nephropathy. We further demonstrate that ANGPTL3 interacts with and activates podocyte-expressed integrin β3 and regulate expression of α-actinin-4, which may result in the cytoskeletal rearrangement of podocytes. Additionally, we identify the activation of the ANGPTL3-integrin β3 signaling pathway in patients with nephrotic syndrome. CONCLUSION: ANGPTL3 might play a crucial role in podocyte injury. Either decreasing ANGPTL3 expression or interfering with the ANGPTL3-integrin β3 interaction might be benefit for podocyte protection and decrease proteinuira.
BACKGROUND:Angiopoietin-like-3 (ANGPTL3) expression is increased in glomerular podocytes of nephrotic syndrome. We hypothesize whether ANGPTL3 plays an important role in podocyte injury and promoting proteinuria. METHODS:Angptl3(+/+) and Angptl3(-/-) female mice on B6;129S5 gene background were injected with adriamycin by tail vein at the dose of 25 mg/Kg to produce nephropathy. Proteinuira was measured and podocytes ultrastructure was observed by electron microscopy. The interaction between ANGPTL3 and intergrin β3 was analyzed by CO-IP and confocal immunofluorescence. The relative gene and protein expression were analyzed by RT-PCR and western blot. RESULTS: The deletion of ANGPTL3 tremendously attenuates proteinuria (more than a fivefold decrease in albuminuria) and protects podocytes from injury in a mouse model of adriamycin-induced nephropathy. We further demonstrate that ANGPTL3 interacts with and activates podocyte-expressed integrin β3 and regulate expression of α-actinin-4, which may result in the cytoskeletal rearrangement of podocytes. Additionally, we identify the activation of the ANGPTL3-integrin β3 signaling pathway in patients with nephrotic syndrome. CONCLUSION:ANGPTL3 might play a crucial role in podocyte injury. Either decreasing ANGPTL3 expression or interfering with the ANGPTL3-integrin β3 interaction might be benefit for podocyte protection and decrease proteinuira.
Authors: Bryce LaFoya; Jordan A Munroe; Alison Miyamoto; Michael A Detweiler; Jacob J Crow; Tana Gazdik; Allan R Albig Journal: Int J Mol Sci Date: 2018-02-02 Impact factor: 5.923