Long-Range Control of Renin Gene Expression in Tsukuba Hypertensive Mice

Abstract

Renin, a rate-limiting enzyme in the renin–angiotensin system, is regulated to maintain blood pressure homeostasis: renin gene expression in the kidney is suppressed in a hypertensive environment. We found that expression of a 15-kb human RENIN (h REN) transgene was aberrantly upregulated (>4.2-fold), while the endogenous mouse renin (m Ren) gene was suppressed (>1.7-fold) in Tsukuba hypertensive mice (THM), a model for genetically induced hypertension. We then generated transgenic mice using a 13-kb m Ren gene fragment that was homologous to the 15-kb h REN transgene and found that its expression was also upregulated (>3.1-fold) in THM, suggesting that putative silencing elements of the renin genes were distally located in the loci. We next examined the possible role of a previously identified mouse distal enhancer (mdE) located outside of the 13-kb m Ren gene fragment. Deletion of the mdE in the context of a 156-kb m Ren transgene did not affect its transcriptional repression in THM, implying that although the silencing element of the m Ren gene is located within the 156-kb fragment tested, it is distinct from the mdE. Consistent with these results, deletion of the 63-kb region upstream of the mdE from the endogenous m Ren gene locus abrogated its transcriptional repression in THM. We finally tested whether dysregulation of the short renin transgenes also occurred in the fetal or neonatal kidneys of THM and found that their expression was not aberrantly upregulated, demonstrating that aberrant regulation of short renin transgenes commences sometime between neonate and adult periods.