Renin Enhancer Is Crucial for Full Response in Renin Expression to an In Vivo Stimulus

Abstract

Abstract-We showed recently that deletion of a strong enhancer located 2.7 kb upstream of the renin gene in mice produces a strain with mild hypotension and salt-sensitivity. Here we set out to compare responses in renin expression in kidney and extrarenal tissues in these "REKO" mice. REKO and wild-type mice were placed on a low NaCl/enalapril regimen for 1 week, and then Ren-1 c mRNA and renin enzyme activities were measured in tissues and plasma. In untreated REKO mice, renin and Ren-1 c mRNA were reduced significantly in kidney, submandibular gland, adrenal, heart, and brain. In situ hybridization indicated a marked reduction in Ren-1 c mRNA in juxtaglomerular cells and granular ducts of submandibular gland. After the chronic stimulus response in renal Ren-1 c mRNA in REKO mice was blunted by 54% compared with wild-type mice, and was accompanied by almost complete exhaustion of renin stores. Response in plasma renin was blunted by 47%, this being mirrored in heart (54% decline), in which renin is derived mostly from the bloodstream. In adrenal a 55% reduction was seen. These data are consistent with inability of REKO mice to adequately replenish renal renin stores during chronic stimulation of renin secretion. In conclusion, the renin enhancer is critical for replenishment of renin stores and response in renin to a chronic in vivo stimulus. Key Words: renin gene expression Ⅲ enhancer Ⅲ knockout mouse Ⅲ low sodium diet Ⅲ angiotensin converting enzyme inhibitor Ⅲ renin mRNA Ⅲ renin enzymatic activity Ⅲ kidney Ⅲ extrarenal renin expression L ocated far upstream of the renin gene of various species is a strong enhancer. 1-5 It has been reported recently that deletion of the mouse 6 or human 7 enhancer in genetically engineered mice leads to a marked reduction in renin in renal juxtaglomerular (JG) cells, which are the classical source of circulating renin. Telemetry studies of mouse renin enhancer knockout (REKO) mice revealed normal diurnal rhythm of blood pressure, but at a mean 9 mm Hg lower level. 6 This was partly normalized by a high NaCl diet. The REKO mice exhibited reduced locomotor activity, normal baroreflex sensitivity, 6 and a blunted cardiovascular response to stress. 8 Here we investigate the response in renin expression of our REKO mice to a strong physiological challenge, namely a low NaCl diet coupled with administration of the ACE inhibitor enalapril, which reduces angiotensin II and thus feedback inhibition of renin secretion. As part of this we measured renin and Ren-1 c mRNA in renal and extrarenal tissues and performed in situ hybridization. Our findings highlight a critical role of the renin enhancer in physiological regulation of renin expression and thus physiological sequelae. Materials and Methods Generation of REKO MiceThe production of REKO mice was as described previously. 6 The experiments described herein were approved by the University of Sydney Animal Ethics Committee. REKO and wild-type (WT; C57BL6) mice were housed in accordance with SPF regulations. In Situ HybridizationReni...

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Transcriptional regulator RBP-J regulates the number and plasticity of renin cells

“…Part of this work was presented at the High Blood Pressure Research Conference, October [13][14][15][16]2010 in Washington, DC, and published in abstract form.…”

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“…62 They exhibited a blunted response in renin mRNA after 1 week of low salt plus enalapril and, as a result, were unable to replace renin stores lost through secretion under these stimulated conditions, therefore explaining their reduced blood pressure. 63 The increase in plasma renin was also blunted, 63 as were stress responses, 64 but not prepulse inhibition. 65 …”