Faculty Collaboration Database

The human renin kidney enhancer is required to maintain base-line renin expression but is dispensable for tissue-specific, cell-specific, and regulated expression. J Biol Chem 2006 Nov 17;281(46):35296-304

Date

09/23/2006

Pubmed ID

16990260

DOI

10.1074/jbc.M608055200

Scopus ID

2-s2.0-33845954722 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

Renin is the rate-limiting enzyme in the renin-angiotensin system and thus dictates the level of the pressor hormone angiotensin-II. The classical site of renin expression and secretion is the renal juxtaglomerular cell, where its expression is tightly regulated by physiological cues. An evolutionarily conserved transcriptional enhancer located 11 kb upstream of the human RENIN gene has been reported to markedly enhance transcription in renin expressing cells in vitro. However, its importance in vivo remains unclear. We tested whether this enhancer is required for appropriate tissue- and cell-specific expression, or for physiological regulation of the human RENIN gene. To accomplish this, we used a retrofitting technique employing homologous recombination in bacteria to delete the enhancer from a 160-kb P1-artificial chromosome containing human RENIN, two upstream genes and one downstream gene, and then generated two lines of transgenic mice. We previously showed that human renin expression in transgenic mice containing the wild type construct is tightly regulated as is expression of the linked genes. Deletion of the enhancer had no effect on tissue-specific expression of human RENIN, but using the downstream gene as an internal control, found that human RENIN mRNA levels were 3-10-fold decreased compared with constructs containing the enhancer. Despite this decrease in expression, renin protein remained localized to renal juxtaglomerular cells and was appropriately regulated by cues that either increase or decrease expression of renin. Our results suggest that sequences other than the enhancer may be necessary for tissue-specific, cell-specific, and regulated expression of human RENIN.

Author List

Zhou X, Davis DR, Sigmund CD

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin-Converting Enzyme Inhibitors
Animals
Blood Pressure
Captopril
Chromosomes, Artificial
Enhancer Elements, Genetic
Gene Expression Regulation
Humans
Kidney
Mice
Mice, Transgenic
Organ Specificity
RNA, Messenger
Renin