FUNCTION OF HUMAN RENIN PROXIMAL PROMOTER DNA

Function of human renin proximal promoter DNA. An understanding of the mechanisms involved in the control of the human renin promoter have b een hampered and confounded in work to date because of deficiencies in material available and experimental design. The promoter appears to b e weak and a good cell model is lacking. Chorio-decidual cultures have been used since these have high renin synthesis, are readily availabl e and grow well in culture. They suffer, however, from phenotypic vari ability and do not transfect well in transient expression analyses. Re cent evidence suggests that 2.6 kb of proximal 5'-flanking DNA is unab le to induce native promoter activity under basal conditions. Experime nts in which an exogenous enhancer was introduced have raised the poss ibility that an endogenous enhancer residing outside of the 2.6 kb 5'- flanking region could be required. Cell-type specific factors also app ear to be needed. The proximal flanking DNA does, however, appear to b e capable of conferring activity on the promoter in chorio-decidual ce lls under stimulated conditions, suggesting that factors so activated may have considerable importance. Evidence suggests that forskolin-res ponsive signal transduction pathways may lead cyclic AMP responsive el ement (CRE) binding protein (CREB) to act on a CRE at -222 in the prox imal REN promoter DNA. Activation of the mouse promoter by cAMP appear s to involve a different element, however. Furthermore, overall contro l of renin synthesis is likely to involve post-transcriptional mechani sms as well. Thus, despite being the first cardiovascular gene to be c loned, much more work is required before the control of the human reni n gene is fully understood.