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Platelet-derived growth factor (PDGF) BB homodimer regulates PDGF A- and PDGF B-chain gene transcription in human mesangial cells.

ABSTRACT: Mesangial cells express platelet-derived growth factor (PDGF) A- and B-chain mRNA and release PDGF. Several polypeptide growth factors, including PDGF itself, induce PDGF A- and B- chain mRNA abundance. To understand the molecular mechanisms associated with the changes in mRNA abundance, we measured the effects of PDGF BB homodimer on PDGF A- and B-chain gene transcription in cultured mesangial cells. The data demonstrate 2- and 4-fold increases in PDGF A-chain gene transcription in response to PDGF BB homodimer at 5 and 24 h time points respectively. PDGF B-chain gene transcription was also induced approximately 3-fold at 2, 5 and 24 h time points in response to treatment with PDGF BB homodimer. The effect of PDGF BB on the half-life of PDGF A- as well as PDGF B-chain mRNA was measured directly by the pulse-chase method. There was no effect on PDGF A-chain mRNA half-life whereas PDGF B-chain mRNA half-life was increased 1.5-fold. These studies indicate that, in human mesangial cells, the increase in the levels of PDGF A- and B-chain mRNA in response to PDGF- receptor(s) activation is mediated at the level of gene transcription. In addition, the regulation of PDGF B- but not PDGF A-chain gene involves increased mRNA stability. Mesangial cells are a useful model for studying molecular mechanisms of PDGF- gene regulation in non-transformed human cells.

SUBMITTER: Bhandari B

PROVIDER: S-EPMC1137841 | biostudies-other | 1994 Jan

REPOSITORIES: biostudies-other

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Project description:Background and purposeSo far, there is only limited information about the regulation of the endogenous synthesis of hydrogen sulfide (H(2) S), an important gaseous signalling molecule. This study was done to evaluate the redox-dependent signalling events that regulate the expression of the H(2) S synthesising enzyme cystathionine-γ-lyase (CSE) in rat mesangial cells.Experimental approachThe effects of platelet-derived growth factor (PDGF)-BB and antioxidants on CSE expression and activity in cultured rat renal mesangial cells were assessed. Activity of nuclear factor erythroid-2-related factor-2 (Nrf2) was measured as the binding capacity to a radiolabelled consensus element by electrophoretic mobility shift assay (EMSA). Furthermore, CSE and Nrf2 expression was analysed in a rat model of anti-Thy-1-induced glomerulonephritis by immunohistochemistry.Key resultsTreatment of mesangial cells with PDGF-BB resulted in a marked time- and dose-dependent up-regulation of CSE mRNA and protein levels, as well as CSE activity accompanied with increased formation of reactive oxygen species. Remarkably, co-administration of antioxidants, such as N-acetylcysteine, ebselen or diphenylene iodonium chloride, drastically reduced PDGF-BB-induced CSE expression. PDGF-BB induced binding of Nrf2 to a corresponding consensus antioxidant element in a redox-dependent manner. Furthermore, PDGF-BB-induced CSE expression in mouse mesangial cells was completely abolished in Nrf2 knockout mice compared with wild-type mice. In a rat model of anti-Thy-1-induced proliferative glomerulonephritis, we observed a marked up-regulation of CSE protein paralleled by a stabilization of Nrf2 protein.Conclusions and implicationsPDGF-BB regulated CSE via a redox-mediated activation of Nrf2. Such action would aid the resolution of glomerular inflammatory diseases.Linked articleThis article is commented on by Gallyas, pp. 2228-2230 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01976.x.

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Platelet-derived growth factor (PDGF) BB homodimer regulates PDGF A- and PDGF B-chain gene transcription in human mesangial cells.

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