Deletion of H-Ras decreases renal fibrosis and myofibroblast activation following ureteral obstruction in mice.
Tubulointerstitial fibrosis is characterized by the presence of myofibroblasts that contribute to extracellular matrix accumulation. These cells may originate from resident fibroblasts, bone-marrow-derived cells, or renal epithelial cells converting to a mesenchymal phenotype. Ras GTPases are activated during renal fibrosis and play crucial roles in regulating both cell proliferation and TGF-beta-induced epithelial-mesenchymal transition. Here we set out to assess the contribution of Ras to experimental renal fibrosis using the well-established model of unilateral ureteral obstruction. Fifteen days after obstruction, both fibroblast proliferation and inducers of epithelial-mesenchymal transition were lower in obstructed kidneys of H-ras knockout mice and in fibroblast cell lines derived from these mice. Interestingly, fibronectin, collagen I accumulation, overall interstitial fibrosis, and the myofibroblast population were also lower in the knockout than in the wild-type mice. As expected, we found lower levels of activated Akt in the kidneys and cultured fibroblasts of the knockout. Whether Ras inhibition will turn out to prevent progression of renal fibrosis will require more direct studies.
Grande
M Teresa
MT
Departamento de Fisiología y Farmacología, Instituto Reina Sofía de Investigación Nefrológica, Universidad de Salamanca, Salamanca 37007, Spain.
Fuentes-Calvo
Isabel
I
Arévalo
Miguel
M
Heredia
Fabiana
F
Santos
Eugenio
E
Martínez-Salgado
Carlos
C
Rodríguez-Puyol
Diego
D
Nieto
M Angela
MA
López-Novoa
José M
JM
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D011905:Genes, ras; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017384:Sequence Deletion; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
D005353:Fibronectins; D016212:Transforming Growth Factor beta; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt