Role of AT1 receptor‐mediated ADAM17 signaling in glutamatergic neurons in neurogenic hypertension
Authors: Xu Jiaxi , Lazartigues Eric 
Published: June 2021

Using a mouse model with Angiotensin II type 1 receptor (AT1R) deletion from neurons in the central nervous system, we previously reported attenuated hypertension, improved autonomic function, and importantly, blunted A Disintegrin And Metalloprotease 17 (ADAM17) activation after deoxycorticosterone‐salt treatment (DOCA 1 mg/g body weight sc + 1% saline po for 3 weeks), compared to non‐transgenic controls. Since neuronal AT1aR has a pivotal role in ADAM17‐mediated ACE2 shedding and the maintenance of neurogenic hypertension, we further investigated the role of central AT1R‐mediated ADAM17 signaling in excitatory neurons, by deleting AT1aR (AT1G) or ADAM17 (A17G) specifically from glutamatergic neurons. AT1G (n=9), A17G (n=8), and controls (n=10) were implanted with telemetry probes for continuous recording of blood pressure (BP). Following DOCA‐salt treatment, all 3 strains showed increased mean arterial pressure, however the pressor responses were significantly lower in both transgenic lines (AT1G: +16 ±3 mmHg, A17G: +21 ±3 mmHg), compared to the controls (+31 ±2 mmHg). Meanwhile, DOCA‐salt treated controls (n=9) exhibited a significant decrease in cardiac systolic function, including ejection fraction (P<0.01 vs. sham) and fractional shortening (P<0.05 vs. sham). Cardiac systolic function remained unchanged in both DOCA‐salt‐treated AT1G (n=9) and A17G (n=5). By the end of DOCA‐salt treatment, baroreflex sensitivity was markedly blunted in the controls (P<0.01 vs. sham), while it was attenuated in A17G (P<0.05 vs. control+DOCA) and completely preserved in AT1G. Baroreflex mediated BP regulation requires both branches of autonomic nervous system. Therefore, sympathetic and parasympathetic tone were assessed in the following experiment. DOCA‐salt‐induced increase in cardiac sympathetic tone was not observed in either AT1G or A17G. Also, vascular sympathetic tone, which can be upregulated in DOCA‐salt hypertension, exhibited no significant change in mice lacking glutamatergic AT1aR or ADAM17. DOCA‐salt‐induced impairment in cardiac vagal tone was still observed in A17G mice (P<0.05 vs. sham), but not in AT1G. Moreover, in AT1G mice, the cardiac vagal tone was found to be significantly upregulated after DOCA‐salt treatment. Intracerebroventricular injection of PD123319, an AT2R antagonist, blocked the excessive vagal tone in DOCA‐salt treated AT1G mice (n=3), suggesting that removal of AT1R from glutamatergic neurons could unmask AT2R signaling. Through mouse blood panel analysis, we found that peripheral immune system was activated during DOCA‐salt hypertension, indicated by increased CD3+, CD45+ and CD3+/CD45+ cell counting. Interestingly, the increased immune cell counting was attenuated in DOCA‐salt treated AT1G and A17G mice. Whether this is due to controlled sympathetic outflow, or it is a secondary to attenuated hypertension, still requires further investigation. In summary, our data provide evidence that AT1aR located on glutamatergic neurons regulate autonomic function and the development of hypertension through ADAM17‐dependent and independent pathways.

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NIH: HL093178; AHA: 15POST25000010

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.