Nuclear factor of activated T-cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes.

Nuclear factor of activated T-cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes. Am J Physiol Renal Physiol. 2013 Feb 6; Authors: Zhu L, Qi XY, Aoudjit L, Mouawad F, Baldwin C, Nattel S, Takano T Abstract Glomerulosclerosis is featured by accumulation of the extracellular matrices in the glomerulus. We showed previously that activation of the small GTPase, RhoA, in podocytes induces heavy proteinuria and glomerulosclerosis in mouse. In the current study, we investigated the mechanism by which RhoA stimulates the production of one of the extracellular matrices, fibronectin, by podocytes, specifically testing the role of nuclear factor of 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 [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 act...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research