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 ([Ca2+]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 [Ca2+]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.

Bone marrow-derived mesenchymal stem cells ameliorate nephrosis through repair of impaired podocytes

“…Jiang et al [44] utilized RhoA inhibitors to suppress the effect of TRPC6 over-expression, implicating RhoA as an important component in TRPC6-induced proteinuria, derangement of podocyte cytoskeleton, decreased expression of nephrin and foot process effacement. Zhu et al [45] also showed that TRPC6 overexpression increases podocyte intracellular calcium to activate RhoA signaling pathways and subsequent kidney damage.…”

Role of Rho-GTPases and their regulatory proteins in glomerular podocyte function

“…These data from cultured podocytes may suggest that the activation of RhoA has a negative impact on podocyte morphology and (or) function. In addition, the albumin-induced transactivation of the endothelin-1 gene in mouse podocytes was dependent on ROCK (Morigi et al 2005), and RhoA-induced activation of the nuclear factor of activated T-cells was shown to contribute to fibronectin gene transactivation in podocytes (Zhu et al 2013). Thus the activation of RhoA may also transactivate pathogenic genes in podocytes.…”

“…In addition, downregulation of nephrin and synaptopodin was demonstrated, which could contribute to proteinuria (Wang et al 2012a). Furthermore, when the expression level of constitutively active RhoA was high it upregulated fibronectin expression and subsequent glomerulosclerosis, possibly via the calcium-calmodulin-calcineurin-NFAT pathway (Zhu et al 2011(Zhu et al , 2013. In the latter context, overexpression of the ECM protein, fibronectin, by injured/simulated podocytes may be indicative of an epithelial-mesenchymal transition to avoid apoptotic cell death (Kang et al 2010).…”

Research progress in acute hypertensive renal injury by “in vivo cryotechnique”

“…When TRPC6 or its upstream signal is blocked, podocyte injury can be alleviated. [26][27][28][29] Connexin43 (Cx43) is a major component of gap junctions (Gjs) and hemichannels, plays a unique role in intracellular communication by directly permitting substances such as calcium, ATP in-and-out of cells. Cx43 also localizes on podocyte SD.…”