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Cytotoxic effects of free fatty acids on mouse podocyte

Other Titles
 마우스 신장 족세포에서 지방산에 의한 세포독성 효과 
Issue Date
Dept. of Medicine/박사
Podocytes play a major role in glomerular filtration barrier, and also participate in pathogenic process of diabetic nephropathy. Diabetic patients have elevated plasma levels of saturated free fatty acid (FFA) that induces ER stress and apoptosis in different cell types. The purpose of this study is to investigate the cytotoxic mechanism of FFA in immortalized mouse podocyte. Incubation with palmitate, a saturated FFA, increased cytosolic and mitochondrial reactive oxygen species (ROS) production and apoptotic cell death in a dose dependent manner. However, a mono-unsaturated FFA oleate itself or combination with palmitate neither increased ROS level nor induced cell death. Palmitate depolarized the mitochondrial membrane potential and reduced ATP generation. As morphodynamic changes, palmitate caused not only a mitochondrial fragmentation but a marked ER lumen dilation. Consistently, palmitate upregulated ER stress proteins such as GRP78/Bip, spliced xbp1 and CHOP. Palmitate depleted the luminal Ca2+ level in ER and abolished the cyclopiazonic acid (CPA)-induced cytosolic Ca2+ increase. Palmitate-induced ER Ca2+ depletion and cytotoxicity were blocked by sulfo-N-succinimidyl oleate (SSO), a selective inhibitor of FAT/CD36 known as a fatty acid transporter. In addition, a mitochondrial antioxidant mitoTEMPO blocked palmitate-induced ER Ca2+ depletion as well as ER stress and partially reduced cytotoxicity. Loss of ER Ca2+ pool induced by palmitate was recovered by inhibitors of phospholipase C (PLC) and protein kinase C, but strongly potentiated by a diacylglycerol (DAG) kinase inhibitor which prevents DAG degradation. Taken together, these data suggest that palmitate as the predominant circulating saturated FFA leads to mitochondrial dysfunction and ER stress through oxidative stress and ER Ca2+ depletion, and these effects might be mediated by FAT/CD36 and PLC signaling in mouse podocyte.
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1. College of Medicine (의과대학) > Others (기타) > 3. Dissertation
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