Activated macrophages down-regulate podocyte nephrin and podocin expression via stress-activated protein kinases |
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Authors: | Ikezumi Yohei Suzuki Toshiaki Karasawa Tamaki Kawachi Hiroshi Nikolic-Paterson David J Uchiyama Makoto |
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Institution: | a Department of Pediatrics, Niigata University Medical and Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku, Asahimachi-dori, Niigata 951-8510, Japan b Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Japan c Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia |
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Abstract: | The development of proteinuria and glomerulosclerosis in kidney disease is associated with podocyte damage, including down-regulation of nephrin and podocin. Macrophages are known to induce renal injury, but the mechanisms involved are not fully understood. This study examined macrophage-mediated podocyte damage. Conditioned media (CM) from activated macrophages caused a 50-60% reduction in nephrin and podocin mRNA and protein expression in cultured mouse podocytes and rat glomeruli. This was abolished by a neutralizing anti-TNFα antibody. The addition of recombinant TNFα to podocytes or glomeruli caused a comparable reduction in podocyte nephrin and podocin expression to that of macrophage CM. Inhibition of c-Jun amino terminal kinase (JNK) or p38 kinase abolished the TNFα-induced reduction in nephrin and podocin expression. This study demonstrates that activated macrophages can induce podocyte injury via a TNFα-JNK/p38-dependent mechanism. This may explain, in part, the protective effects of JNK and p38 blockade in experimental kidney disease. |
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Keywords: | TNF-α JNK p38 MAPK NF-κB IFN-γ Cytoskeleton |
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