Reduction of Gstm1 expression in the stroke-prone spontaneously hypertension rat contributes to increased oxidative stress

TY - JOUR

T1 - Reduction of Gstm1 expression in the stroke-prone spontaneously hypertension rat contributes to increased oxidative stress

AU - McBride, Martin W.

AU - Brosnan, M. Julia

AU - Mathers, Joanne

AU - McLellan, Lesley I.

AU - Miller, William H.

AU - Graham, Delyth

AU - Hanlon, Neil

AU - Hamilton, Carlene A.

AU - Polke, James M.

AU - Lee, Wai K.

AU - Dominiczak, Anna F.

N1 - dc.publisher: American Heart Association

PY - 2005/4

Y1 - 2005/4

N2 - Human essential hypertension is a classic example of a complex, multifactorial, polygenic disease with a substantial genetic influence in which the underlying genetic components remain unknown. The stroke-prone spontaneously hypertension rat (SHRSP) is a well-characterized experimental model for essential hypertension and endothelial dysfunction. Previous work, identified glutathione S-transferase µ type 1, a protein involved in detoxification of reactive oxygen species, as a positional and functional candidate gene. Quantitative real-time polymerase chain reaction showed a highly significant, 4-fold reduction of glutathione S-transferase µ type 1 mRNA expression in 5- and 16-week-old SHRSP compared with the congenic and normotensive Wistar Kyoto rats. This suggests that differential expression is not attributable to long-term changes in blood pressure. DNA sequencing identified one coding single nucleotide polymorphism (R202H) and multiple single nucleotide polymorphisms in the promoter region. mRNA expression changes were reflected at the protein level, with significant reductions in the SHRSP glutathione S-transferase µ type 1. Protein was colocalized with aquaporin 2 to the principle cells of the renal collecting ducts. Coupled to significant increases in nitrotyrosine levels in the kidney, this suggests a pathophysiological role of this protein in hypertension and oxidative stress. Similar processes may underlie oxidative stress in the vasculature.

AB - Human essential hypertension is a classic example of a complex, multifactorial, polygenic disease with a substantial genetic influence in which the underlying genetic components remain unknown. The stroke-prone spontaneously hypertension rat (SHRSP) is a well-characterized experimental model for essential hypertension and endothelial dysfunction. Previous work, identified glutathione S-transferase µ type 1, a protein involved in detoxification of reactive oxygen species, as a positional and functional candidate gene. Quantitative real-time polymerase chain reaction showed a highly significant, 4-fold reduction of glutathione S-transferase µ type 1 mRNA expression in 5- and 16-week-old SHRSP compared with the congenic and normotensive Wistar Kyoto rats. This suggests that differential expression is not attributable to long-term changes in blood pressure. DNA sequencing identified one coding single nucleotide polymorphism (R202H) and multiple single nucleotide polymorphisms in the promoter region. mRNA expression changes were reflected at the protein level, with significant reductions in the SHRSP glutathione S-transferase µ type 1. Protein was colocalized with aquaporin 2 to the principle cells of the renal collecting ducts. Coupled to significant increases in nitrotyrosine levels in the kidney, this suggests a pathophysiological role of this protein in hypertension and oxidative stress. Similar processes may underlie oxidative stress in the vasculature.

KW - Stroke-prone hypertension rat (SHR)

KW - Hypertension

KW - Gene expression

KW - Oxidative stress

KW - Genetic

KW - Rats

KW - SHR

U2 - 10.1161/01.HYP.0000154879.49245.39

DO - 10.1161/01.HYP.0000154879.49245.39

M3 - Article

SN - 0194-911X

VL - 45

SP - 786

EP - 792

JO - Hypertension

JF - Hypertension

IS - 4

ER -