ALTERED NUCLEAR-PROTEIN BINDING TO THE FIRST INTRON OF THE RENIN GENEOF THE SPONTANEOUSLY HYPERTENSIVE RAT

We and others have reported elevated levels of renin mRNA in extrarena l tissues of the spontaneously hypertensive rat (SHR) of the Okamoto s train. We hypothesise that this is due to mutations we have found in p utative, cis-regulatory regions in the first intron of its renin gene. Here we report two G-A mutations at position +502 and +934 of the fir st intron of the SHR renin gene, when compared to normotensive Wistar Kyoto (WKY) and Sprague Dawley (SD) rats. These mutations fall within consensus sequences for the well described E2A and peroxisome prolifer ator-activated receptor (PPAR) transcription factors. We used electrop horetic mobility shift assays to determine if these mutations alter th e pattern or affinity of nuclear protein binding to oligonucleotides h omologous to these regions of the renin gene. Both mutations significa ntly altered the intensity and pattern of nuclear protein binding to o ligonucleotides homologous with the renin gene regions bearing these p utative transcription factor binding sites, Thus these mutations have the potential to alter the type and/or affinity of transcriptional fac tors for the SHR renin gene in vivo, and result in renin overproductio n at an extra-renal tissue site subserving blood pressure control.