1. Nerve growth factor exposure promotes tubular epithelial-mesenchymal transition via TGF-β1 signaling activation.
- Author
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Vizza D, Perri A, Toteda G, Lupinacci S, Leone F, Gigliotti P, Lofaro D, La Russa A, and Bonofiglio R
- Subjects
- Active Transport, Cell Nucleus physiology, Antibodies immunology, Cell Line, Cell Movement, Epithelial Cells cytology, Humans, Nerve Growth Factor blood, Nerve Growth Factor immunology, Nerve Tissue Proteins metabolism, RNA Interference, RNA, Small Interfering genetics, Receptor, trkA metabolism, Receptors, Nerve Growth Factor metabolism, Smad3 Protein antagonists & inhibitors, Smad3 Protein immunology, Smad3 Protein metabolism, Smad4 Protein antagonists & inhibitors, Smad4 Protein immunology, Smad4 Protein metabolism, Transcription, Genetic genetics, Transforming Growth Factor beta1 genetics, Epithelial-Mesenchymal Transition physiology, Fibrosis pathology, Kidney Tubules physiology, Nerve Growth Factor metabolism, Renal Insufficiency, Chronic pathology, Transforming Growth Factor beta1 metabolism
- Abstract
Clinical studies showed that renal expression and serum levels of nerve growth factor (NGF) are increased in renal diseases characterized by progressive fibrosis, a pathologic process in which TGF-β1 mediates most of the key events leading to tubular epithelial-mesenchymal transition (EMT). However, the pathogenic role of high NGF levels has not yet been elucidated. In this study, we found that in tubular renal cells, HK-2, NGF transcriptionally up-regulated TGF-β1 expression and secretion and enhanced cell motility by activating EMT markers via its receptors, TrkA and p75(NTR). Interestingly, we observed that TGF-β1-SMAD pathway activation and the up-regulation of EMT markers NGF-induced were both prevented when knockdown of TGF-β1 gene occurred and that the pretreatment with an antibody anti-NGF reversed the nuclear translocation of pSMAD3/SMAD4 complex. Collectively, our results demonstrated that NGF promotes renal fibrosis via TGF-β1-signaling activation, suggesting that in kidney diseases high NGF serum levels could contribute to worsen renal fibrosis.
- Published
- 2015
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