Reduction of Gstm1 expression in the stroke-prone spontaneously hypertension rat contributes to increased oxidative stress.
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 mu 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 mu 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 mu 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.
McBride
Martin W
MW
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom.
Brosnan
M Julia
MJ
Mathers
Joanne
J
McLellan
Lesley I
LI
Miller
William H
WH
Graham
Delyth
D
Hanlon
Neil
N
Hamilton
Carlene A
CA
Polke
James M
JM
Lee
Wai K
WK
Dominiczak
Anna F
AF
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001120:Arginine; D015153:Blotting, Western; D003199:Computer Systems; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006639:Histidine; D006973:Hypertension / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics*; D011921:Rats, Inbred WKY; D020521:Stroke / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism
D001120:Arginine; D005982:Glutathione Transferase; D006639:Histidine; D013481:Superoxides