BMP-7 protects mesangial cells from injury by polymeric IgA.
Bone morphogenetic protein-7 (BMP-7) is a potential therapeutic agent for acute and chronic renal diseases. Here we found that addition of polymeric IgA, isolated from patients with IgA nephropathy, increased the synthesis of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta (TGF-beta) and fibronectin in cultured human mesangial cells, effects blunted by BMP-7. When mesangial cells were cultured with both polymeric IgA and BMP-7 there was an increase in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The activation of NF kappaB and TNF-alpha synthesis induced by polymeric IgA or TNF-alpha were downregulated by BMP-7 or rosiglitazone. BMP-7 inhibited TNF-alpha release from polymeric IgA-stimulated mesangial cells by activation of PPAR-gamma but suppressed TGF-beta release by mechanisms independent of PPAR-gamma. The expression of inhibitory Smad6 and 7 was increased whereas the expression of active Smad2 and 3 was reduced in these mesangial cells by BMP-7. Our study shows that BMP-7 ameliorates IgA nephropathy-derived polymeric IgA-induced TNF-alpha and TGF-beta synthesis in human mesangial cells through multiple mechanisms involving inhibitory Smads and PPAR-gamma.
Chan
Wai Long
WL
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
Leung
Joseph C K
JC
Chan
Loretta Y Y
LY
Tam
K Y
KY
Tang
Sydney C W
SC
Lai
Kar Neng
KN
D055419:Bone Morphogenetic Protein 7 / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005922:Glomerulonephritis, IGA / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000494:pharmacology*; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects
D055419:Bone Morphogenetic Protein 7; D007070:Immunoglobulin A; D047495:PPAR gamma; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C034639:polymeric IgA