[No authors listed]
BACKGROUND:Combined congenic breeding and microarray gene expression profiling previously identified glutathione S-transferase μ-type 1 (Gstm1) as a positional and functional candidate gene for blood pressure (BP) regulation in the stroke-prone spontaneously hypertensive (SHRSP) rat. Renal Gstm1 expression in SHRSP rats is significantly reduced when compared with normotensive Wistar Kyoto (WKY) rats. As Gstm1 plays an important role in the secondary defence against oxidative stress, significantly lower expression levels may be functionally relevant in the development of hypertension. The aim of this study was to investigate the role of Gstm1 in BP regulation and oxidative stress by transgenic overexpression of the Gstm1 gene. METHOD:Two independent Gstm1 transgenic SHRSP lines were generated by microinjecting SHRSP embryos with a linear construct controlled by the EF-1α promoter encoding WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1 and SHRSP-Tg(Gstm1)2]. RESULTS:Transgenic rats exhibit significantly reduced BP and pulse pressure when compared with SHRSP [systolic: SHRSP 205.2â±â3.7âmmHg vs. SHRSP-Tg(Gstm1)1 175.5â±â1.6âmmHg and SHRSP-Tg(Gstm1)2 172â±â3.2âmmHg, Pâ<â0.001; pulse pressure: SHRSP 58.4â±â0.73âmmHg vs. SHRSP-Tg(Gstm1)1 52.7â±â0.19âmmHg and SHRSP-Tg(Gstm1)2 40.7â±â0.53âmmHg, Pâ<â0.001]. Total renal and aortic Gstm1 expression in transgenic animals was significantly increased compared with SHRSP [renal relative quantification SHRSP-Tg(Gstm1)1 1.95 vs. SHRSP 1.0, Pâ<â0.01; aorta SHRSP-Tg(Gstm1)1 2.8 vs. SHRSP 1.0, Pâ<â0.05]. Renal lipid peroxidation (malondialdehyde: protein) and oxidizedâ:âreduced glutathione ratio levels were significantly reduced in both transgenic lines when compared with SHRSP [malondialdehyde: SHRSP 0.04â±â0.009âμmol/l vs. SHRSP-Tg(Gstm1)1 0.024â±â0.002âμmol/l and SHRSP-Tg(Gstm1)2 0.021â±â0.002âμmol/l; (oxidizedâ:âreduced glutathione ratio): SHRSP 5.19â±â2.26âμmol/l vs. SHRSP-Tg(Gstm1)1 0.17â±â0.11âμmol/l and SHRSP-Tg(Gstm1)2 0.47â±â0.22âμmol/l]. Transgenic SHRSP rats containing the WKY Gstm1 gene demonstrate significantly lower BP, reduced oxidative stress and improved levels of renal Gstm1 expression. CONCLUSION:These data support the hypothesis that reduced renal Gstm1 plays a role in the development of hypertension.
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