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Differential regulation of connective tissue growth factor in renal cells by histone deacetylase inhibitors.

ABSTRACT: Regulation of the profibrotic and angiogenesis modulating cytokine connective tissue growth factor (CTGF) occurs primarily at the transcriptional level. Therefore, we hypothesized that histone deacetylating enzymes (HDAC), which modulate the accessibility of transcriptionally active promoter regions, might play a role in the regulation of CTGF gene expression. We analyzed microvascular endothelial cells, which showed immunoreactivity for acetylated histone in kidney sections, and compared them with renal tubular epithelial cells. Treatment of cultured endothelial cells with different HDAC inhibitors up-regulated CTGF mRNA and protein. Pre-treatment with HDAC inhibitors facilitated induction of CTGF by transforming growth factor-beta (TGF-beta) or lysophosphatidic acid. Transcription factors of the FoxO family were involved in the up-regulation of CTGF as shown at protein level and by reporter gene analyses. In tubular epithelial cells, up-regulation of CTGF was only observed when these cells were cultured as subconfluent cells. Dense cells, which are more likely to resemble tubular cells in vivo, showed no up-regulation upon treatment with HDAC inhibitors and were protected against CTGF induction by TGF-beta. Taken together, our data indicate that the effect of HDAC inhibitors on CTGF expression is largely cell dependent in non-tumour cells. Different cell type-specific transcription factors seem to determine whether CTGF expression is reduced or increased in cells exposed to HDAC inhibitors.

SUBMITTER: Komorowsky C

PROVIDER: S-EPMC9181358 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Differential regulation of connective tissue growth factor in renal cells by histone deacetylase inhibitors.

Komorowsky Claudiu C Ocker Matthias M Goppelt-Struebe Margarete M

Journal of cellular and molecular medicine 20090801 8B

Regulation of the profibrotic and angiogenesis modulating cytokine connective tissue growth factor (CTGF) occurs primarily at the transcriptional level. Therefore, we hypothesized that histone deacetylating enzymes (HDAC), which modulate the accessibility of transcriptionally active promoter regions, might play a role in the regulation of CTGF gene expression. We analyzed microvascular endothelial cells, which showed immunoreactivity for acetylated histone in kidney sections, and compared them w ...[more]

PMID: 20141616

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Project description:In lupus nephritis (LN), kidney inflammation may be followed by fibrosis and progressive decline in function. Transforming growth factor (TGF)-β is a notable mediator of fibrosis, but it has other beneficial roles, thus indicating a need for alternate therapeutic targets for inhibition of fibrosis. Connective tissue growth factor (CTGF) acts as a downstream mediator of TGF-β in promoting fibrosis, without mediating the immunosuppressive effects of TGF-β. Animal studies show that CTGF may have important roles in renal fibrosis, but data are limited in human subjects. The present study tested the hypothesis that renal CTGF mRNA expression is related to TGF-β1 and collagen I expression and is predictive of renal function deterioration in patients with LN (n=39). Gene expression was measured using multiplex real-time quantitative RT-PCR and renal function was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular filtration rate (GFR) equation. Decline in GFR was assessed by regression of GFR at biopsy to 1 year following biopsy. CTGF mRNA expression was significantly correlated with TGF-β1 and collagen I. GFR at biopsy was 89.2±39.2 ml/ min. Renal CTGF mRNA expression correlated inversely with baseline GFR. Renal CTGF mRNA was significantly higher in patients with moderate to severe CKD compared to those in the milder CKD group (low GFR 4.92±4.34 vs. high GFR 1.52±1.94, p<0.005). CTGF mRNA was also higher in patients with subsequent decline in GFR [GFR decline (5.19±4.46) vs. no GFR decline (1.79±1.97); P<0.01]. In conclusion, renal expression of CTGF was positively related to TGF-β1 and collagen I in patients with LN. Furthermore, high CTGF mRNA expression was associated with poor GFR at baseline and subsequent deterioration of kidney function. CTGF expression in the kidney may serve as an early marker for renal disease progression and could be evaluated as a target for therapeutic intervention to prevent renal failure in LN.

Dataset Information

Differential regulation of connective tissue growth factor in renal cells by histone deacetylase inhibitors.

Publications

Differential regulation of connective tissue growth factor in renal cells by histone deacetylase inhibitors.

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