Activated macrophages down-regulate podocyte nephrin and podocin expression via stress-activated protein kinases.
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-TNFalpha antibody. The addition of recombinant TNFalpha 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 TNFalpha-induced reduction in nephrin and podocin expression. This study demonstrates that activated macrophages can induce podocyte injury via a TNFalpha-JNK/p38-dependent mechanism. This may explain, in part, the protective effects of JNK and p38 blockade in experimental kidney disease.
Ikezumi
Yohei
Y
Department of Pediatrics, Niigata University Medical and Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku, Asahimachi-dori, Niigata 951-8510, Japan. ikezumi@med.niigata-u.ac.jp
Suzuki
Toshiaki
T
Karasawa
Tamaki
T
Kawachi
Hiroshi
H
Nikolic-Paterson
David J
DJ
Uchiyama
Makoto
M
D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017077:Culture Media, Conditioned; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases