title: Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes.
abstract: Glomerulosclerosis is featured by accumulation of the extracellular matrixes in the glomerulus. We showed previously that activation of the small GTPase RhoA in podocytes induces heavy proteinuria and glomerulosclerosis in the mouse. In the current study, we investigated the mechanism by which RhoA stimulates the production of one of the extracellular matrixes, fibronectin, by podocytes, specifically testing the role of nuclear factor of activated T cells (NFAT). Expression of constitutively active RhoA in cultured podocytes activated the fibronectin promoter, upregulated fibronectin protein, and activated NFAT. Expression of constitutively active NFAT in podocytes also activated the fibronectin promoter and upregulated fibronectin protein. RhoA-induced NFAT activation and fibronectin upregulation were both dependent on the calcium/calmodulin pathway and Rho kinase. NFAT activation was also observed in vivo in the rat and mouse models of podocyte injury and proteinuria, and NFAT inhibition ameliorated fibronectin upregulation in the latter. RhoA activation induced a rise of intracellular calcium ion concentration ([Ca(2+)]i), which was at least in part dependent on the transient receptor potential canonical 6 (TRPC6) cation channel. The results indicate that RhoA activates NFAT by inducing a rise of [Ca(2+)]i in podocytes, which in turn contributes to fibronectin upregulation. This pathway may be responsible for the pathogenesis of certain glomerular diseases such as hypertension-mediated glomerulosclerosis.
authors: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
authors: Lei
authors: L
authors: Zhu
authors: Xiao-Yan
authors: XY
authors: Qi
authors: Lamine
authors: L
authors: Aoudjit
authors: Flaviana
authors: F
authors: Mouawad
authors: Cindy
authors: C
authors: Baldwin
authors: Stanley
authors: S
authors: Nattel
authors: Tomoko
authors: T
authors: Takano
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D051381:Rats; D050052:TRPC Cation Channels / Q000235:genetics / Q000502:physiology; D000074287:TRPC6 Cation Channel; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D005353:Fibronectins; D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D020742:rhoA GTP-Binding Protein; D002118:Calcium