Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial fibrosis is a marker of progression of renal impairment in diabetic nephropathy. Transforming growth factor (TGF)-beta 1 is one of a group of pro-fibrotic cytokines and growth factors that have been associated with the development of interstitial fibrosis. We have examined the modulating influence of glucose on the production of TGF-beta 1 by cultured human proximal tubular cells. Incubation of growth-arrested human proximal tubular cells (HPTC) (72 hours in serum free medium) in 25 mmol/L D-glucose resulted in increased expression of TGF-beta 1 mRNA (as assessed by reverse transcription polymerase chain reaction). This was apparent after 6 hours and increased up to 120 hours exposure. TGF-beta 1 secretion, however, as measured by specific enzyme-linked immunoassay, was unaffected by exposure to 25 mmol/L D-glucose. Sequential stimulation of HPTC, first with 25 mmol/L D-glucose for 48 hours and then with platelet-derived growth factor (PDGF) isoforms, resulted in a dose-dependent secretion of TGF-beta 1. Pre-exposure to 5 mmol/L D-glucose or 25 mmol/L L-glucose did not prime for TGF-beta 1 release. At 50 ng/ml PDGF this effect was greatest for the AA isoform (AA 31.4 +/- 7.1, AB 20.98 +/- 8.9, BB 7.8 +/- 2.2, P < 0.05 for all versus control, n = 3, mean +/- SEM ng/10(6) cells/24 hours). These effects were blocked by the addition of antibody to the PDGF alpha-receptor. TGF-beta 1 secretion was inhibited in a dose-dependent manner by pretreatment with cyclohexamide, but was not affected by pretreatment with actinomycin D. Stimulation of HPTC with a single dose of PDGF induced TGF-beta 1 mRNA; however, only after application of a second dose of PDGF (after TGF-beta 1 mRNA induction) did TGF-beta 1 protein secretion occur. We also demonstrated that PDGF stimulation of HPTC induced an inherently more stable TGF-beta 1 mRNA transcript. These findings demonstrate that elevated D-glucose concentration alone is insufficient to lead to increased TGF-beta 1 secretion by HPTC despite increased mRNA expression. However, application of a second stimulus such as PDGF, when TGF-beta 1 mRNA expression is increased, leads to increased protein synthesis and secretion of TGF-beta 1. This implies that elevated glucose concentrations might prime proximal tubular cells for TGF-beta 1 synthesis and thus contribute to the development of interstitial fibrosis.
 ...
PMID:Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. 763 30

Interstitial fibrosis is significantly correlated with the progression of renal impairment for most causes of renal insufficiency. Transforming growth factor beta 1 (TGF-beta 1) and basic fibroblast growth factor (bFGF) are two of a group of profibrotic cytokines that have been associated with the development of renal interstitial fibrosis. We have previously demonstrated that alterations in D-glucose concentrations modulate the synthesis of TGF-beta 1 by human renal proximal tubular cells (HPTC) in vitro. The aim of the present study was to examine the influence of bFGF on TGF-beta 1 synthesis by HPTC in culture and to examine any modulation of this response by changes in ambient glucose concentration. Incubation of growth-arrested HPTC (72 hours in serum-free medium) with bFGF resulted in a dose-dependent increase in latent TGF-beta 1 secretion. Maximal release of TGF-beta 1 was seen at a bFGF dose of 50 ng/ml in cells incubated in 5 mM D-glucose (7.48 +/- 2.5 ng/ml, mean +/- SEM; n = 3; p = 0.04). This release of TGF-beta 1 in response to bFGF was unaffected by increasing the concentration of glucose in the culture media to 25 mM (7.76 +/- 1.3, mean +/- SEM; n = 3; p < 0.02). It was also unaffected by pretreatment of cells with either actinomycin-D or cycloheximide. TGF-beta 1 secretion was, however, inhibited in a dose-dependent manner by the exposure of cells to the microtubule-disrupting agent vinblastine, indicating that the generation of TGF-beta 1 was dependent on the secretion of preformed, stored TGF-beta 1. In a separate series of experiments, exposure of HPTC to TGF-beta 1 (10 ng/ml) led to the induction of bFGF mRNA, which was first apparent at 12 hours and reached maximal levels 24 hours after stimulation (normalized bFGF/alpha-actin mRNA ratio was 1.5 times that of the control). This increase in bFGF mRNA was accompanied by a time-dependent increase in bFGF protein production, which was maximal after 24 hours (19.83 +/- 12.7 pg/ml versus 2.49 +/- 0.34 pg/ml, mean +/- SEM, stimulated versus control; n = 3; p = 0.03). These findings demonstrate that bFGF stimulates the secretion of preformed, latent TGF-beta 1 by HPTC but does not induce de novo TGF-beta 1 gene transcription or TGF-beta 1 protein synthesis. We have also demonstrated a positive-feedback loop involving TGF-beta 1 and bFGF and postulate that this may be involved in the progressive nature of renal fibrosis in vivo.
 ...
PMID:Basic fibroblast growth factor stimulates the release of preformed transforming growth factor beta 1 from human proximal tubular cells in the absence of de novo gene transcription or mRNA translation. 911 19