Selective knockout of novel intracellular renin isoform results in reduced adiposity

Abstract

Renin gene expression is regulated by two distinct promoter / first exon combinations that target renin for either secretion (exon 1a) or for cytoplasmic retention (exon 1b). Renin‐1b is expressed predominantly in the brain and is differentially regulated from renin‐1a in response to stimuli such as deoxycorticosterone (DOCA)‐salt. Mice were generated that lack exon 1b (and thereby intracellular renin, icREN‐KO) but retain exon 1a. Male icREN‐KO mice were similar in size (n=4, 14.7±0.9 wk, 27.94±1.08 g) compared to littermate controls (n=7, 14.2±0.8 wk, 27.96±0.82 g, P=0.988), but by NMR exhibited reduced total and relative total fat mass (1.83±0.15 vs 3.00±0.12 g, or 6.6±0.7 vs 10.9±0.5 %, both P<0.001). Interestingly, interscapular brown adipose (289±77, n=5 vs 68±61 mg, n=9 P=0.04) and heart (162±12 vs 129±9 mg, P=0.04) masses were both increased in icREN‐KO mice, possibly suggesting increased resting metabolic rate (RMR) and blood pressure. Liver and kidney masses were normal. Food intake was normal (3.25±0.28, n=4 vs 3.14±0.14, n=8 P=0.7), but preliminary tests uncovered trends toward increased RMR (7.67±0.75, n=4 vs 6.93±0.59 g/day, n=4 kcal/kg lean/hr, P=0.47) and glucose tolerance (2g/kg, 25768±3994, n=3 vs 33734±2854 mg/dL*min, n=8, P=0.157). Together these data suggest that the novel icREN isoform contributes to metabolic control.