Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism

Abstract

The brain specific isoform of renin (Ren-b), has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to DOCA-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after DOCA-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not due to changes in food intake, energy absorption or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue (BAT), suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased BAT glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.

Role of brain renin angiotensin system in neurodegeneration: An update

“…Cellular and molecular studies have reported that all RAS genes and their promoter regions are active in the brain, while other evidences also revealed the de novo production of RAS components in the brain (Hermann et al, 1987;Fuxe et al, 1980). The establishment of brain RAS is also supported by several pharmacological inhibition studies (Shinohara et al, 2016(Shinohara et al, , 2017. Similarly, it has been found that all the components required for the synthesis of angiotensin peptides are synthesized locally within the brain (Harding et al, 1988).…”

“…However, van Thiel et al suggested that intracellular renin could be the key to generation of angiotensins in the brain, and coordinate other non-RAS functions (van Thiel et al, 2017). In addition, the impaired activity or expression of the brain renin may cause neurogenic hypertension, altering drinking and metabolism (Shinohara et al, 2016(Shinohara et al, , 2017. Few studies though still suggest that the expression of renin is controversial in the brain .…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…In vitro and in vivo experiments suggest this form of renin is indeed active (546,555,973). Nevertheless, the physiological significance of endogenous intracellular renin remains unclear because, surprisingly, deletion of renin-b caused hypertension and increased activity of the brain RAS (954,955).…”

Integrative Physiological Aspects of Brain RAS in Hypertension

“…These data demonstrate that the secreted version of renin (Renin-a) is dispensable within the brain for cardiovascular, fluid, and metabolic homeostasis. Knockout of renin-b resulted in an increase in BP and sympathetic nerve activity and impaired baroreflex sensitivity as demonstrated by Shinohara et al [6]. These authors proposed the hypothesis that in the brain, renin-b inhibits renin-a expression under normal conditions.…”

“…Moreover, the authors showed an increase in Ang II activity in renin knockout mice, suggesting that Ang II formation might occur by other proteases, such as cathepsin [84,85]. In addition to the above cardiovascular effects, Shinohara et al [6] recently demonstrated that Renin-b is also important in the regulation of energy homeostasis and thermogenesis. The authors showed an increase in resting metabolic rate and SNA to brown adipose tissue in renin-b null mice.…”