title: Molecular biology of human renin and its gene.
abstract: This article describes investigations of several aspects of the molecular biology of the human renin gene and the three-dimensional structure of renin and its precursor, prorenin. Because of the importance of the RAS in hypertension, heart failure, renal failure, and possibly other disorders such as atherosclerosis, it is critical to understand the detailed control of this system. This control involves regulation at the transcriptional level, folding of prorenin, sorting of prorenin to a regulated pathway where it is proteolytically cleaved to renin and released in response to secretogogues, constitutive release of uncleaved prorenin, and nonproteolytic activation of prorenin. Currently there is great interest not only in the control of renin in the kidney, the sole source of circulating renin, but also at extrarenal sites where RAS activity may regulate cardiovascular functions. The renin gene was found to be expressed significantly in the renal juxtaglomerular cells and several other cell types. Most tissue culture cells did not express the gene; exceptions were cultured SK-LMS-1 cells and cAMP-stimulated human lung fibroblasts. Cultured human uterine-placental cells expressed the human renin gene at levels higher than in other cell types assessed. Renin mRNA had the same start site in the placental cells as the kidney and was regulated by calcium ionophores and cAMP. Thus, these cells provide primary nontransformed human cells to study the homologous human promoter. Transfected renin promoters showed cell type-specific expression and cAMP responsiveness in these cells in constructs containing as few as 102 bp of 5'-flanking DNA. DNA upstream from this appears to contain an inhibitory element(s) that may have some tissue specificity in its distribution. The cAMP response is not due to cAMP induction of a transcription factor that secondarily affects the renin promoter. A novel element may be involved, since the promoter does not contain a CRE element that mediates many cAMP responses, and the cells do not appear to respond to another known cAMP-responsive transcription factor, AP-2. Studies with transfected vectors expressing a mutant cAMP-responsive protein kinase A regulatory subunit suggest that cAMP is not responsible for basal renin promoter activity in the placental cells. By contrast, cAMP induces in essence gene activation in WI26VA4 transformed human lung fibroblasts in which renin mRNA levels increase by up to 150-fold in response to forskolin. Thus, cAMP may activate renin gene expression under certain circumstances and tissue-specific renin gene expression may be directed by more than one mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Metabolic Research Unit, University of California, San Francisco.
authors.forename: J D
authors.initials: JD
authors.lastname: Baxter
authors.forename: K
authors.initials: K
authors.lastname: Duncan
authors.forename: W
authors.initials: W
authors.lastname: Chu
authors.forename: M N
authors.initials: MN
authors.lastname: James
authors.forename: R B
authors.initials: RB
authors.lastname: Russell
authors.forename: M A
authors.initials: MA
authors.lastname: Haidar
authors.forename: F M
authors.initials: FM
authors.lastname: DeNoto
authors.forename: W
authors.initials: W
authors.lastname: Hsueh
authors.forename: T L
authors.initials: TL
authors.lastname: Reudelhuber
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011994:Recombinant Proteins; D012083:Renin / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D011994:Recombinant Proteins; D004247:DNA; D012083:Renin