NUCLEOTIDE VARIATIONS IN INTRON-1 OF THE RENIN GENE OF THE SPONTANEOUSLY HYPERTENSIVE RAT

The renin gene is known to be overexpressed in the spontaneously hyper tensive rat (SHR) of the Okamoto strain. As the first intron of many g enes controls transcription rate, we examined whether the first 1,100 base pairs of the SHR first intron possessed mutations in putative tra nscriptional factor binding sites. Such mutations might then form the basis for overexpression of the renin gene in the SHR. A BglII restric tion fragment length polymorphism (RFLP) was identified in the first 1 ,100 base pairs of the first intron of the renin gene of the SHR when compared to Wistar Kyoto (WKY) and Sprague Dawley (SD) normotensive ra ts. Sequence analysis of this region located the BglII RFLP between po sitions 501-505 of the rat renin gene. The new BglII cut site was prod uced by a single base mutation from G to A at position 502. While a nu mber of other insertional and deletional events were found in the SHR, WKY and SD sequences over this region, only two were unique to the SH R. These mutations occurred at positions 191, 502, 934 and 1070. The l atter three fell within sequence motifs known to bind the transcriptio nal factors PPAR, E2A and AP2 respectively. Thus we propose that these mutations alter the DNA binding characteristics of one or more transc riptional factors to the SHR renin gene first intron resulting in its overexpression which, in turn, might form the basis for a tissue renin -angiotensin dependent hypertension in this strain.