Involvement of Calcineurin in Transforming Growth Factor-β-mediated Regulation of Extracellular Matrix Accumulation

Gooch, Jennifer; Gorin, Yves; Zhang, Bin Xian; Abboud, Hanna E.

doi:10.1074/jbc.m308759200

Cited by 94 publications

(105 citation statements)

References 53 publications

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“…Consistent with this finding, recent data show that increases in intracellular calcium are observed in cell populations treated with TGF-␤. Moreover, these calcium shifts were sufficient to activate calcineurin (47). Other published data show (48,49) that TGF-␤ can either stimulate or inhibit calcium mobilization and calcium signaling.…”

Section: Discussionmentioning

confidence: 72%

FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Reinhold

Abe

Kapadia

et al. 2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 72%

FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Reinhold

Abe

Kapadia

et al. 2004

Journal of Biological Chemistry

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“…9 The CaN/ NFATc pathway was thought to play an important role in TGF-b-mediated induction of glomerular hypertrophy and FN expression, which is in agreement with other literature reporting that administration of CaN inhibitor CsA blocked accumulation of both CaN protein and CaN activity and substantially reduced ECM accumulation and hypertrophy in diabetic glomeruli. 10,11 We have found that NCTD can alleviate the expression of CaN in tubules in DN. 6 However, CaN is primarily expressed in the epithelium of proximal tubules.…”

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 99%

“…CaN is a calcium/calmodulindependent serine/threonine phosphatase that participates in a number of cellular processes and Ca 2 þ -dependent signal transduction pathways. Gooch et al [9][10][11] demonstrated that CaN expression was increased in the diabetic kidney and played an important role in the progression of glomerulosclerosis in DN. In addition, inhibition of CaN by cyclosporine (CsA) could reduce glomerular hypertrophy and block extracellular matrix (ECM) accumulation, such as fibronectin (FN), collagen IV (ColIV), and so on, in glomuruli.…”

mentioning

confidence: 99%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

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“…1,2 This protein is a heterodimer which consists of a regulatory subunit, known as calcineurin B (CNB), and a catalytic subunit, known as calcineurin A (CNA). 3 At least three isoforms have been cloned for the catalytic subunit of CNA; CNA-a, CNA-b 4 and CNA-g (also named PPP3CC).…”

Section: Introductionmentioning

confidence: 99%

More evidence supports the association of PPP3CC with schizophrenia

et al. 2007

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Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B (CNB) and a catalytic subunit of calcineurin A (CNA). PPP3CC is the c isoform of CNA located at the chromosome 8p21.3 region. To evaluate the association between PPP3CC and schizophrenia in the Taiwanese population, 10 single nucleotide polymorphism (SNP) markers across the gene were genotyped by the method of MALDI-TOF in 218 schizophrenia families with at least two affected siblings. One SNP (rs2272080) located around the exon 1 untranslated region was nominally associated with schizophrenia (P = 0.024) and significantly associated with the expression of PPP3CC in lymphoblast cell line; the TT and TG genotype had significantly higher relative expression levels than the GG genotype (P = 0.0012 and 0.015, respectively). In further endophenotype stratification, the single locus of rs2272080 and the haplotypes of both two-SNP haplotype (rs7833266-rs2272080) and seven-SNP haplotype (rs2461491-rs2469758-rs2461489-rs2469770-rs2449340-rs1482337-rs2252471) showed significant associations with the subgroup of schizophrenia with deficits of the sustained attention as tested by the continuous performance test (CPT, P < 0.05) and the executive functioning as tested by the Wisconsin Card Sorting Test (WCST, P < 0.05). The results suggest that PPP3CC gene may be a true susceptibility gene for schizophrenia.

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Involvement of Calcineurin in Transforming Growth Factor-β-mediated Regulation of Extracellular Matrix Accumulation

Cited by 94 publications

References 53 publications

FGF18 Represses Noggin Expression and Is Induced by Calcineurin

FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

More evidence supports the association of PPP3CC with schizophrenia

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