A Novel Interaction Between Sympathetic Overactivity and Aberrant Regulation of Renin by miR-181a in BPH/2J Genetically Hypertensive Mice

Abstract

BPH/2J mice are a genetic model of hypertension developed by Schlager 1 by crossing 8 normotensive strains and selecting for elevated blood pressure (BP). Normotensive BPN/3J control mice were bred concurrently by crossing randomly selected mice from the same base population. Recently, the mechanism of the hypertension has been recognized as neurogenic because ganglion blockade abolished the hypertension in BPH/2J mice.2 Furthermore, spectral analysis of BP revealed greater power in the autonomic frequency band, suggesting overactivity of the sympathetic nervous system (SNS), most prominently during the nocturnal active period.2 BPH/2J mice also display exaggerated daynight differences in BP, which are associated with greater neuronal activity in regions of the hypothalamus and amygdala known to be important for cardiovascular regulation. Given the recent success of renal sympathetic nerve ablation for the treatment of resistant hypertension, 3 the importance of renal influences on the expression of neurogenic hypertension has been highlighted. Importantly, the peripheral renin-angiotensin system (RAS) is closely linked to renal sympathetic nerve activity (RSNA) via its ability to stimulate renin secretion, 4 and also through angiotensin II-mediated facilitation of SNA. 5 However, the interaction of the kidney and renal RAS with SNS-mediated hypertension in BPH/2J mice has not been investigated thoroughly. The role of the RAS has been examined in a variety of ways in BPH/2J mice including by measurement of messenger RNA (mRNA) in tissues and various pharmacological assessments. [6][7][8][9][10] Iwao et al 8 reported normal renin activity in plasma, kidney, and submandibular gland of BPH/2J mice, although others found greater renin activity Abstract-Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the reninangiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg IP) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg IP) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2...

Comparison of different normalization strategies for the analysis of glomerular microRNAs in IgA nephropathy

“…Whole tissue analysis of human nephrectomy specimens has shown that the tubular expression of miR-181a-5p is associated with renin mRNA expression3940. This is in accordance with the finding of an aberrant renal miR-181a-5p expression in mouse41 and human40 hypertensive kidneys. In our small cohort without any differences in arterial blood pressure miR-181a-5p was stably expressed in lasermicrodissected glomeruli with IgA nephropathy, indicating that miR-181a-5p is not primarily affected by IgA-GN or neighboring crescents.…”

Actions of rilmenidine on neurogenic hypertension in BPH/2J genetically hypertensive mice

“…Additionally, low-dose AngII-induced hypertension in rabbits, which is accompanied by elevated RSNA, is shown to be associated with greater long-term neuronal activation of the PVN but not the RVLM [60]. This AngII-induced hypertensive model may be particularly similar to the BPH/2J mice since our recent findings also suggest that the hypertension in BPH/2J mice is caused by a greater contribution of the systemic renin-angiotensin system caused by renal hyper-innervation and greater sympathetically induced renin synthesis [61]. Indeed, our own previous findings indicate greater neuronal activity in the PVN but not the RVLM of BPH/2J compared with BPN/3J mice during periods of arousal [1].…”

Signatures of miR-181a on the Renal Transcriptome and Blood Pressure

“…Both reduced renal expression of miR-181a and an increase in renin mRNA abundance were associated with hypertension in a small collection of human kidneys (9). miR-181a exhibited an inverse correlation with renin in a genetically hypertensive strain of mice (10). Taken together, these data strongly suggest that this miRNA may constitute a new posttranscriptional layer of control for the ratelimiting enzyme of the renin-angiotensin system (RAS) and, as such, may contribute to BP regulation, thus making it an attractive target for the development of new antihypertensive therapies.…”