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High-lipid Induced Endoplasmic Reticulum Stress and Inflammatory Factor Caused the Podocyte Injure through NPC1 and Its Mechanism
Xiong Xiao, Xiao Lei, Yang Xuejun, Yan Junli, Yang Haiping, Li Qiu*
Department of Nephroimmunology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, China
Abstract: The goals of this study is to investigate the role of lipid-induced endoplasmic reticulum stress (ERS) in podocyte injury under inflammatory condition and to explore whether it is related to intracellular cholesterol transporters Niemann-pick C1 protein (NPC1). Podocytes were cultured and divided into control group，low-density lipoprotein (LDL) group， IL-1β+LDL group， tunicamycin group (TM)， 4-phenyl butyric acid (4-PBA) group and statin group. The apoptosis of podocytes was measured by flow cytometry. The accumulation of lipid droplet in the cells was detected by oil red O staining. The mRNA leves of NPC1， glucose-regulated protein78 (GRP78)， protein kinase R-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) were determined by real-time PCR. GRP78 protein level was detected by immunofluorescence assay. We found that inflammation increased the rate of lipid-induced apoptosis in a time and dose dependent manners. Co-treatment of cells with high levels of lipid and IL-1β significantly increased the intracellular lipid accumulation and the levels of GRP78， PERK， ATF6， NPC1 mRNA. Pretreatment of cells with low concentrations of TM and 4-PBA significantly decreased apoptosis rate and down-regulated GRP78， PERK， ATF6 expression， while statin and 4-PBA treatment can reduce NPC1 expression and intracellular lipid accumulation. These results suggested that lipid might be transported to ER by NPC1 and its accumulation in ER promotes podocyte injury through activating ERS under inflammatory conditions. Reduction of ERS and the intacellular accumulation of lipid droplet can alleviate the damages on podocytes.
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