Oleate induces a myofibroblast-like phenotype in mesangial cells.
OBJECTIVE
High circulating free fatty acids, commonly associated with obesity and insulin resistance, impair structure and function of the microvasculature. However, the mechanisms by which fatty acids cause microvascular remodeling are unclear. Using the mesangial cell model of microvascular pericytes, we demonstrate that the monounsaturated free fatty acid oleate induces a myofibroblast phenotype, an important cell fate transition in fibrotic remodeling of the extracellular matrix.


RESULTS
Oleate induced a time- and dose-dependent increase in secretion of collagen I and fibronectin. Oleate also induced the myofibroblast phenotype markers alpha smooth muscle actin and ED-A fibronectin, and the magnitude of marker protein expression was similar to that for transforming growth factor (TGF)-beta. Oleate raised TGF-beta secretion 2.2-fold, and processing of latent to bioactive TGF-beta was also elevated. Oleate rapidly stimulated extracellular signal-regulated kinase1/2, and a pharmacological MEK inhibitor blocked TGF-beta secretion and conversion to the myofibroblast phenotype. A neutralizing TGF-beta antibody and a TGF-beta receptor kinase inhibitor blocked oleate-induced collagen I, alpha smooth muscle actin, and ED-A fibronectin, suggesting that oleate-stimulated TGF-beta was necessary for inducing myofibroblasts.


CONCLUSIONS
Collectively, these results demonstrate that oleate can induce a myofibroblast phenotype in mesangial cells, which suggests a mechanism whereby elevated free fatty acids might promote microvascular remodeling in vivo.
Mishra
Rangnath
R
Division of Nephrology and Hypertension, Department of Medicine, Case Western Reserve University and University Hospital Case Medical Center, Cleveland, OH 44106, USA.
Simonson
Michael S
MS
D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005353:Fibronectins / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D050527:Mesangial Cells / Q000187:drug effects* / Q000502:physiology; D019301:Oleic Acid / Q000494:pharmacology*; D010641:Phenotype; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*
D024042:Collagen Type I; D005353:Fibronectins; D016212:Transforming Growth Factor beta; D019301:Oleic Acid