Targeting ADAM17 on Microglia Enhances Baroreflex Gain in Salt Sensitive Hypertension

Microglia, the resident immune cell in the brain, contributes to neuroinflammation and neurogenic hypertension by secreting various cytokines and chemokines. ADAM17 shedding of these signaling molecules in microglia modulates synaptic function but the consequences of this process have not been studied in neurogenic hypertension. Accordingly, we hypothesize that deletion of ADAM17 in microglia prevents microglia activation, thus preserving the baroreflex gain and blunting the development of salt-sensitive hypertension. To test our hypothesis, a new mouse model (MAT-/-) amenable for selective deletion of ADAM17 in microglia was developed. Following the initiation of deoxycorticosterone acetate plus salt (DOCA-salt) hypertension, tamoxifen was injected intracerebroventricularly to delete ADAM17 selectively in microglia and blood pressure (BP) monitored over 3 weeks. Spontaneous Baroreflex Sensitivity (SBRS) was calculated using the sequence method (Hemolab). In mice lacking ADAM17 in microglia, the mean arterial pressure increase induced by DOCA-salt treatment was blunted compared to control MAT+/+ mice (127.4 ±5 vs. 143.4 ±4 mmHg, n=13, p<0.05). While baseline SBRS was not different between groups (MAT-/-: 4.1 ±1, MAT+/+: 3.1 ±0.6 msec/mmHg, n=10, p>0.05) and DOCA implantation produced a similar reduction of SBRS (MAT-/-: 2.5 ±0.6 vs. MAT+/+: 2.3 ±0.6 msec/mmHg, p<0.05), deletion of microglia ADAM17 following tamoxifen icv injection improved SBRS in MAT-/- mice compared to MAT+/+ (SBRS: 3.6 ±1 vs. 2.3±0.5 msec/mmHg, Student’s t-test, p<0.05) suggesting that ADAM17 in microglia regulates baroreflex gain. Moreover, conditional deletion of ADAM17 from microglia was associated with significant (p<0.05) reductions of BDNF (MAT-/-: 11.8 ±1.4 vs. MAT+/+: 17.7 ±2.2 pg/mL), vasopressin (MAT-/-: 2.3 ±0.2 vs. MAT+/+: 2.7 ±0.4 pg/mL), neuropeptide Y (MAT-/-: 2.5 ±0.6 vs. MAT+/+: 23.7 ±13.8 pg/mL) levels and ACE2 activity (MAT-/-: 2.5 ±0.71 vs. MAT+/+: 3.3 ±1.3 FU/min/nM/mL) in the plasma. In addition, in isolated microglia, DOCA-Salt treated MAT-/- had higher ACE2 protein expression compared to MAT+/+ (1.6 ±0.2 vs. 0.6 ±0.2, p<0.05). Together, knockdown of ADAM17 specifically on microglia blunted the development of hypertension by preserving ACE2 activity, preventing BDNF, neuropeptide Y and vasopressin release, protecting baroreflex gain and decreasing sympatho-excitation. Thus, we conclude that ADAM17 in microglia plays a pivotal role in salt sensitive hypertension. This work was supported in part by a research grant from the National Institutes of Health (HL163588) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.