Smooth muscle alpha-actin deficiency in myofibroblasts leads to enhanced renal tissue fibrosis.
Myofibroblasts are a major source of proinflammatory cytokines and extracellular matrix in progressive tissue fibrosis leading to chronic organ failure. Myofibroblasts are characterized by de novo expression of smooth muscle alpha-actin (SMalphaA), which correlates with the extent of disease progression, although their exact role is unknown. In vitro cultured myofibroblasts from kidney of SMalphaA knock-out mice demonstrate significantly more prominent cell motility, proliferation, and type-I procollagen expression than those of wild-type myofibroblasts. These pro-fibrotic properties are suppressed by adenovirus-mediated SMalphaA re-expression, accompanied by down-regulation of focal adhesion proteins. In interstitial fibrosis model, tissue fibrosis area, proliferating interstitial cell number, and type-I procollagen expression are enhanced under SMalphaA deficiency. In mesangioproliferative glomerulonephritis model, cell proliferation in the mesangial area is also enhanced in SMalphaA knock-out mice. Adenoviral SMalphaA introduction into renal interstitium obviously ameliorates tissue fibrosis in interstitial fibrosis model. These results indicate that SMalphaA suppresses the pro-fibrotic properties of myofibroblasts, highlighting the significance of smooth muscle-related proteins in moderating chronic organ fibrosis under pathological conditions.
Takeji
Masanobu
M
Genome Information Research Center, Research Institute for Microbial Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Moriyama
Toshiki
T
Oseto
Susumu
S
Kawada
Noritaka
N
Hori
Masatsugu
M
Imai
Enyu
E
Miwa
Takeshi
T
D000199:Actins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000235:genetics; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology*; D009395:Nephritis, Interstitial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D000199:Actins