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Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor.
Am J Pathol. 1995 Aug; 147(2):362-74.AJ

Abstract

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.

Authors+Show Affiliations

Institute of Nephrology, University of Wales College of Medicine, Cardiff Royal Infirmary, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7639330

Citation

Phillips, A O., et al. "Elevated D-glucose Concentrations Modulate TGF-beta 1 Synthesis By Human Cultured Renal Proximal Tubular Cells. the Permissive Role of Platelet-derived Growth Factor." The American Journal of Pathology, vol. 147, no. 2, 1995, pp. 362-74.
Phillips AO, Steadman R, Topley N, et al. Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. Am J Pathol. 1995;147(2):362-74.
Phillips, A. O., Steadman, R., Topley, N., & Williams, J. D. (1995). Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. The American Journal of Pathology, 147(2), 362-74.
Phillips AO, et al. Elevated D-glucose Concentrations Modulate TGF-beta 1 Synthesis By Human Cultured Renal Proximal Tubular Cells. the Permissive Role of Platelet-derived Growth Factor. Am J Pathol. 1995;147(2):362-74. PubMed PMID: 7639330.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. AU - Phillips,A O, AU - Steadman,R, AU - Topley,N, AU - Williams,J D, PY - 1995/8/1/pubmed PY - 1995/8/1/medline PY - 1995/8/1/entrez SP - 362 EP - 74 JF - The American journal of pathology JO - Am. J. Pathol. VL - 147 IS - 2 N2 - 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. SN - 0002-9440 UR - https://www.unboundmedicine.com/medline/citation/7639330/Elevated_D_glucose_concentrations_modulate_TGF_beta_1_synthesis_by_human_cultured_renal_proximal_tubular_cells__The_permissive_role_of_platelet_derived_growth_factor_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/7639330/ DB - PRIME DP - Unbound Medicine ER -