© 1999 American Heart Association, Inc.
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Distinct Renin Isoforms Generated by Tissue-Specific Transcription Initiation and Alternative Splicing
From the Cardiovascular Division (M.A.L.-K., K.L.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Universitätskinderklinik (M.A.L.-K.), Technische Universität, Dresden, Germany; and Max-Delbrück Centre for Molecular Medicine (F.G., M.C.C., K.L.), Berlin, Germany.
Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, Mass 02115. E-mail kl{at}calvin.bwh.harvard.edu
Abstract—The aspartyl protease renin catalyzes the initial and rate-limiting step in the formation of the biologically active peptide angiotensin II. It is mainly synthesized in the kidney as a preprohormone and secreted via constitutive and regulated pathways. We identified a novel transcript of the rat renin gene, renin b, characterized by the presence of an alternative first exon (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 assays, we mapped the transcriptional start site of this novel mRNA within intron 1 of the rat genomic sequence, suggesting the presence of a brain-specific promoter within intron 1. The presence of a brain-specific renin isoform is evolutionally conserved, as demonstrated by the finding of renin b isoforms in mice and humans. The predicted protein renin b lacks the prefragment as well as a significant portion of the profragment and is therefore predicted not to be a secreted protein, unlike the classically described isoform renin a. As shown by in vitro translation of full-length renin b mRNA in the presence of microsomal membranes, renin b was not targeted into the endoplasmatic reticulum and remained intracellularly in transiently transfected AtT-20 cells. These findings provide evidence for a novel pathway of intracellular angiotensin generation that occurs exclusively in the brain.
Key Words: renin • renin-angiotensin system • alternative splicing • gene expression • brain
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