Molecular pharmacological study about mechanisms of increased AT1 receptor expression in the brain of spontaneously hypertensive rats

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The angiotensin type 1 (AT1) receptor gene is overexpressed in the brain of spontaneously hypertensive rats (SHR) and this overexpression of the receptor is an important causal factor for hypertension in SHR. We examined whether there are mutations responsible for the overexpression of the AT1 receptor gene in SHR AT1 receptor promoter region. Sequence analysis identified one single base mutation unique to the SHR AT1 receptor gene promoter region when compared to that of Wistar Kyoto rats (WKY). Electrophoretic mobility shift assay (EMSA) showed that there were 3 major similar DNA protein complexes against WKY and SHR oligonucleotide. Additionally, the oligonucleotide bearing the SHR sequence produced an extra band. However, promoter/luciferase reporter assay demonstrated that the promoter activity of SHR AT1 receptor promoters (-2050 to +57) was lower than that of WKY. Next, we examined whether changes in the level of the transcriptional factors responsible for AT1 receptor gene expression are involved in the overexpression of the AT1 receptor gene hi SHR brain. EMSA showed that Sp1 and AP2 are increased in nuclear extracts of hypothalamus from SHR. Spl decoy phosphorothioate oligodeoxynucleotides injected into the lateral ventricle produced a decreased in blood pressure in SHR. The findings suggest that Sp1 and AP2 levels are increased in the hypothalamus of SHR. These change in Sp1 an AP2 might be involved in developmen of hypertension in SHR.