Abstract 080: Selective Knockout of the Intracellular Isoform of Renin in the Brain Contributes to Metabolic and Cardiovascular Control

Abstract

Renin gene expression is regulated by two distinct promoter-first exon combinations that target renin for either secretion (exon 1a initiating secreted renin, sREN) or for cytoplasmic retention (exon 1b initiating intracellular renin, icREN). The icREN isoform is expressed predominantly in the brain and its expression is downregulated whereas sREN expression is upregulated by deoxycorticosterone (DOCA)-salt suggesting each isoform may be differentially regulated. We generated mice that lack icREN, but preserve sREN, by flanking exon-1b and its surrounding sequences (including the promoter) with loxP sites and breeding successively with mice expressing flipase and cre-recombinase. Real time quantitative RT-PCR analysis revealed a loss of icREN mRNA in the brain, but a preservation of sREN mRNA in the kidney. Total body weight was normal in male icREN-KO mice (26.3±0.7 g, n=8, 12 wk) compared to controls (25.3±0.7 g, n=12, 12 wk), but total (2.14±0.09 g vs 2.46±0.11 g) and relative (9.0±0.5 % vs 10.7±0.6%) fat mass as measured by NMR were reduced in 8-week icREN-KO mice (n=14-16, P<0.05). Whereas food intake was normal, there was an increase in resting metabolic rate as measured by respirometry in icREN-KO (0.1484±0.0036 kcal/hr, n=41, P=0.02 by ANCOVA) vs controls (0.1389±0.0038 kcal/hr, n=38). There was also a trend toward decreased digestive efficiency (81.1±1.0%, n=6, P=0.06) vs controls (84.9±1.2%, n=3) at 22 wk of age. Systolic blood pressure was decreased in icREN-KO mice (113±1 mmHg, n=12, 17.0±1.2 wk vs 120±3 mmHg, n=5, 15.9±1.9 wk, P<0.05). We previously reported a functional link between the synthesis and action of angiotensin-II and the action of leptin. We tested if this was impaired in icREN-KO mice by measuring the renal sympathetic nerve activity (RSNA) response to acute intracerebroventricular (ICV) administration of leptin. The decrease in arterial pressure was confirmed in this cohort of icREN-KO mice. Surprisingly, the RSNA response to leptin was greater in icREN-KO mice compared to controls (257.9±16.0%, n=3 vs 157.0±13.9%, n=4, 4 hr after leptin, P=0.01). Captopril attenuated the sympathetic response to ICV leptin. Together these data suggest that this novel icREN isoform contributes to metabolic and cardiovascular control.