Transforming growth factor-β ₁ hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage

Abstract

Hypertension, a remediable risk factor for stroke, cardiovascular disease, and renal failure, affects 50 million individuals in the United States alone. African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Herein, we explored the hypotheses that transforming growth factor-beta(1) (TGF-beta(1)) is hyperexpressed in hypertensives compared with normotensives and that TGF-beta(1) overexpression is more frequent in blacks compared with whites. These hypotheses were stimulated by our recent demonstration that TGF-beta(1) is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients and by the biological attributes of TGF-beta(1), which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGF-beta(1) is produced in excess. TGF-beta(1) profiles were determined in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. Our investigation demonstrated that TGF-beta(1) protein levels are highest in black hypertensives, and TGF-beta(1) protein as well as TGF-beta(1) mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 (Pro(10)) was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGF-beta(1) mRNA and protein. Our findings support the idea that TGF-beta(1) hyperexpression is a risk factor for hypertension and hypertensive complications and provides a mechanism for the excess burden of hypertension in blacks.

Relationship between transforming growth factor β1 and progression of hypertensive renal disease

“…Overproduction of TGF␤1 has been experimentally linked to the sequela of chronic hypertension, including vascular remodelling and progressive renal disease. 11,22 Moreover experimental data have also demonstrated that high circulating levels of this cytokine can mediate organ and tissue damage. 23,24 The exact mechanism by which TGF␤1 activity is enhanced in hypertensive renal disease is not yet clear, but an overproduction of TGF␤1 has been reported to be mediated by angiotensin II.…”

“…The biological actions of TGF␤1 and the reported association with renal pathology support the hypothesis that increased frequency of TGF␤1-overproduction is a candidate mechanism for progression of hypertensive renal disease to end-stage renal disease. 11 In view of this, it has been recently reported that some antihypertensive drugs such as angiotensinconverting enzyme (ACE) inhibitors decrease TGF␤1 levels, and that changes in TGF␤1 values may predict the course of diabetes nephropathy. 27 Accordingly, it should be possible to select a subset of hypertensive subjects (with higher levels of TGF␤1) who are more responsive to the treatment and characterised by a possible slow progression of renal disease.…”

“…8 Only few clinical studies have been designed to evaluate the role of TGF␤1 in human hypertension. [9][10][11][12] Accordingly, the aim of the present study is to evaluate the relationship between circulating TGF␤1 and progression of renal damage in a population of hypertensive subjects.…”

Association of transforming growth factor- 1 gene polymorphism in the development of Epstein-Barr virus-related hematologic diseases

“…The codon 10 is an important site for the regulation of TGF-β1 gene expression and the C allele at this site was reported to be linked to high levels of TGF-β1 mRNA and its protein. 19,20 In fact, Suthanthiran et al reported that both mRNA and protein levels of TGF-β1 in the population were higher among subjects genotyped as C/C or C/T at codon 10 compared with those genotyped as T/T. 19 Thus, the polymorphism causing an amino acid substitution from leucine to proline might influence TGF-β1 protein secretion, which up-regulates its own transcription via AP-1 sites located in its promoter.…”

Transforming Growth Factor .BETA.1 +869T/C Gene Polymorphism and Essential Hypertension: A Meta-analysis Involving 2708 Participants in the Chinese Population

“…The +869T/C gene polymorphism was located in exon 1 and encoded the signal peptide of TGFB1 which was indispensable to the secretion and translation of proteins. The +869T/C transition caused a leucine to proline substitution which likely increased the secretion rates of TGFB1 by influencing the transcription and expression of TGFB1 gene (6)(7)(8).…”