J. D. Baxter, K. Duncan, W. Chu, M. N. James, R. B. Russell, M. A. Haidar, F. M. DeNoto, W. Hsueh & T. L. Reudelhuber
Molecular biology of human renin and its gene.
From Recent Prog. Horm. Res., 47, 257-258
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.