Distinct renin isoforms generated by tissue-specific transcription initiation and alternative splicing

The aspartyl protease renin catalyzes the initial and rate-limiting step in the formation of the biologically active peptide angiotensin II. It is mai nly synthesized in the kidney as a preprohormone and secreted via constitut ive and regulated pathways. We identified a novel transcript of the rat ren in gene, renin b, characterized by the presence of an alternative first exo n (exon 1b) that is spliced to exon 2 of the known transcript, termed renin a. We demonstrated that renin b is exclusively expressed in the brain. In contrast, renin a was not expressed in the brain. Using primer extension as says, we mapped the transcriptional start site of this novel mRNA within in tron 1 of the rat genomic sequence, suggesting the presence of a brain-spec ific promoter within intron 1. The presence of a brain-specific renin isofo rm is evolutionally conserved, as demonstrated by the finding of renin b is oforms in mice and humans. The predicted protein renin b lacks the prefragm ent as well as a significant portion of the profragment and is therefore pr edicted not to be a secreted protein, unlike the classically described isof orm renin a. As shown by in vitro translation of full-length renin b mRNA i n the presence of microsomal membranes, renin b was not targeted into the e ndoplasmatic reticulum and remained intracellularly in transiently transfec ted AtT-20 cells. These findings provide evidence for a novel pathway of in tracellular angiotensin generation that occurs exclusively in the brain.