Abstract 634: Selective Genetic Deletion of the Brain-Specific Intracellular Renin Isoform (Renin-1b) Results in Altered Metabolic and Fluid Balance Regulation

Abstract

An evolutionarily-conserved mRNA initiating with an alternative first exon (exon 1b) of the renin gene codes for an active renin enzyme that should be targeted to the cytoplasm instead of the cellular export apparatus. This intracellular renin (icREN) is expressed primarily in brain and is regulated independently from the traditional secreted isoform of renin (sREN), which is encoded by a mRNA initiated at the traditional first exon (exon 1a). We have developed two mouse models containing conditional alleles of either exon 1a (knocking out sREN and preserving icREN) and exon 1b (knocking out icREN and preserving sREN), thus allowing for global and site-selective knockout (KO) of the individual renin isoforms. icREN-KO mice (n=5, vs n=8 littermate controls) exhibit a trend toward reduced body mass (25.1±2.3 vs 29.0±1.0 g) despite normal food intake (3.2±0.3 vs 2.9±0.9 g/day). During a two-bottle choice between water and 0.15 M NaCl, icREN-KO mice exhibit, at baseline, normal total fluid intake (3.4±0.8 vs 2.8±0.4 mL/day), total sodium intake (0.7±0.2 vs 0.6±0.1 mEq/day), and preference for 0.15 M NaCl (47.6±11.0 vs 42.8±9.5 %). Following an 18-hour dehydration, icREN-KO mice exhibit a trend toward increased water intake (1.5±0.3 vs 1.1±0.2 mL/2hr) that is exaggerated when normalized to their smaller body size (63±15 vs 37±7 mL/kg/2hr). Despite normal 5-hour fasted blood glucose (202±6 vs 214±11 mg/dL), icREN-KO mice exhibit markedly improved glucose tolerance (2 mg/kg ipGTT; 18,540±4,937 vs 33,003±2,578 mg/dL*min, P=0.02). Ongoing studies include measurement of resting metabolic rate under baseline conditions, and assessment of all of the above endpoints following chronic treatment of icREN-KO mice with deoxycorticosterone acetate and high dietary sodium (DOCA-salt treatment). Interestingly, DOCA-salt treated C57BL/6 mice also exhibit improved glucose tolerance (39,901±2,198 vs 31,712±1,722 mg/dL*min, P<0.01) and exhibit a 60% decrease in icREN mRNA expression in the brain. These data introduce for the first time a mouse with selective ablation of intracellular renin and provide the first experimental support for physiologically-relevant functions of intracellular renin.