NFATc is required for TGFβ-mediated transcriptional regulation of fibronectin

Cobbs, Scott L.; Gooch, Jennifer

doi:10.1016/j.bbrc.2007.07.186

Cited by 31 publications

(32 citation statements)

References 22 publications

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“…It should be noted, however, that the response to NFAT activation is highly cell dependent. For example, it was shown that calcineurin/NFAT mediates TGF-␤-induced fibronectin upregulation in glomerular mesangial cells while it has the opposite impact in tubular cells (10). Our results definitively identified NFAT as a stimulant of fibronectin production in podocytes in a TGF-␤-independent manner.…”

Section: Discussionsupporting

confidence: 68%

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

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

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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.

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Section: Discussionsupporting

confidence: 68%

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

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

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“…These results thus demonstrated that SIRT3 plays a role in regulating the TGF-␤1 signaling. In addition to TGF-␤ signaling, tissue fibrosis can also be promoted by activation of transcription factors like ␤-catenin and NFATc (23)(24)(25)(26). We therefore measured expression of these factors in Sirt3-KO hearts.…”

Section: Resultsmentioning

confidence: 99%

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan

Bindu

Pillai

et al. 2016

Molecular and Cellular Biology

160

141

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Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor ␤1 (TGF-␤1)-mediated transformation of fibroblasts into myofibroblasts, cells capable of synthesizing extracellular matrix. Here, we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the profibrotic TGF-␤1 signaling. We found that Sirt3 knockout (KO) mice with age develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs but not whole-body SIRT3-overexpressing mice. SIRT3 deficiency caused induction of TGF-␤1 expression and hyperacetylation of glycogen synthase kinase 3␤ (GSK3␤) at residue K15, which negatively regulated GSK3␤ activity to phosphorylate the substrates Smad3 and ␤-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3␤ and thereby blocked TGF-␤1 signaling and tissue fibrosis. These data reveal a new role of SIRT3 to negatively regulate aging-associated tissue fibrosis and discloses a novel phosphorylation-independent mechanism controlling the catalytic activity of GSK3␤.

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“…Another research found that there is only a small amount of CaN expression in a normal kidney, mainly in renal proximal tubules. 18 Gooch et al 19,20 reported that CaN expression in kidney tissue increased, and the activity of CaN phosphatase also upregulated in the early stage of diabetes. CaN played an important role in glomerulosclerosis of DN, and inhibiting CaN could obviously alleviate the degree of glomerulosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Chen

Liu

et al. 2011

Renal Failure

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Objective: To investigate the effects of norcantharidin (NCTD) on tubulointerstitial fibrosis of diabetic nephropathy (DN) in streptozotocin-induced rat model. Methods: Sprague-Dawley rats were randomly divided into control group, model group, low-dose NCTD (0.05 mg/kg/day) group, and high-dose NCTD (0.1 mg/kg/day) group. The model group was induced by injection intraperitoneally with 30 mg/kg streptozotocin in 0.1 mol/L sodium citrate solution (pH 4.5), after high-calorie foods were given for 2 months. NCTD was administered daily after the DN rat model was built. Rats were sacrificed at the end of the third and the eighth week; renal fibrosis and the expression of FN, collagen IV, TGF-b1, and calcineurin (CaN) were detected by Masson and immunohistochemistry staining, respectively. Results: Tubulointerstitial fibrosis was observed in DN rats, this kind of pathological changes was ameliorated in NCTD treatment group (p < 0.05). The expressions of FN, collagen IV, and TGF-b1 protein increased in the tubulointerstitial field of DN rats compared with the rats in control group. NCTD treatment could dose-dependently decrease their expression and reverse the fibrotic degree (p < 0.05). Meanwhile, the expression of CaN was detected in tubular fields of normal kidney and increased in the tubulointerstitial field in DN rats. However, NCTD downregulated its expression in a dosedependent manner (p < 0.05). Conclusions: NCTD could downregulate FN, collagen IV, and TGF-b1 expression in tubulointerstitial fields and attenuate tubulointerstitial fibrosis in the early stage of DN rats. NCTD also alleviated the expression of CaN in tubules in DN. The relationship between the role of NCTD's anti-tubulointerstitial fibrosis and its inhibition to CaN expression remains to be further elucidated.

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NFATc is required for TGFβ-mediated transcriptional regulation of fibronectin

Cited by 31 publications

References 22 publications

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

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

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