Transgenic overexpression of glutathione S-transferase μ-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat
Background: Combined congenic breeding and
microarray gene expression profiling previously identified
glutathione S-transferase m-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-1a promoter encoding
WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1WKY and SHRSPTg(Gstm1)2WKY].
Results: Transgenic rats exhibit significantly reduced BP and
pulse pressure when compared with SHRSP [systolic: SHRSP
205.2 3.7 mmHg vs. SHRSP-Tg(Gstm1)1WKY
175.5 1.6 mmHg and SHRSP-Tg(Gstm1)2WKY
172 3.2 mmHg, P< 0.001; pulse pressure: SHRSP
58.4 0.73 mmHg vs. SHRSP-Tg(Gstm1)1WKY
52.7 0.19 mmHg and SHRSP-Tg(Gstm1)2WKY
40.75 0.53 mmHg, P< 0.001]. Total renal and aortic
Gstm1 expression in transgenic animals was significantly
increased compared with SHRSP [renal relative quantification
(RQ): SHRSP-Tg(Gstm1)1WKY 1.95 vs. SHRSP 1.0, P< 0.01;
aorta RQ: SHRSP-Tg(Gstm1)1WKY 2.8 vs. SHRSP 1.0,
P< 0.05]. Renal lipid peroxidation (malondialdehyde: protein)
and oxidized : reduced glutathione ratio levels were
significantly reduced in both transgenic lines when compared
with SHRSP [malondialdehyde: SHRSP 0.04 0.009mmol/l
vs. SHRSP-Tg(Gstm1)1WKY 0.024 0.002mmol/l and SHRSPTg(Gstm1)2WKY
0.021 0.002mmol/l; (oxidized : reduced
glutathione ratio): SHRSP 5.19 2.26mmol/l vs. SHRSPTg(Gstm1)1WKY
0.17 0.111mmol/l and SHRSPTg(Gstm1)2WKY
0.471 0.223mmol/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
