Selective deletion of ADAM17 in microglia prevented the development of salt-sensitive hypertension, significantly decreasing mean arterial blood pressure (92 vs 109 mmHg) and sympathetic activity.
Deletion of ADAM17 in microglia prevents the development of salt-sensitive hypertension, reduces sympathetic nerve activity, and decreases cardiac and renal fibrosis in mice.
Absolute Event Rate: 92% vs 109%
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. We aimed to elucidate the role of ADAM17 in regulating microglial activity, which can modulate sympathetic nerve activity, blood pressure and neuroinflammation. To test our hypothesis, a new mouse model (MAT-/-) amenable for selective deletion of ADAM17 in microglia was developed. Uni-nephrectomized male mice (14–16-week-old) with selective deletion of ADAM17 in microglia (MAT-/-) or littermate controls (MAT+/+) were injected with tamoxifen (400 nl ICV) to initiate ADAM17 deletion from microglia. After recovery from surgery, mice received a deoxycorticosterone acetate pellet subcutaneously (DOCA, 50 mg) plus 1% salt in drinking water (DS). After 3 weeks of DS treatment, mice were euthanized, and the brains were collected. BP measured in anesthetized mice, showed a significant decrease in systolic, diastolic, and mean arterial BP in the MAT-/-DS group (106 ± 5; 74 ± 2; and 92 ± 4 mmHg, respectively) compared to the MAT+/+DS group (129 ± 7; 85 ± 3; and 109 ± 5 mmHg). These values were not significantly different from the MAT+/+ sham-treated group (105 ± 3; 73 ± 2; and 89 ± 2 mmHg) and stressed the importance of ADAM17 in microglia since its absence prevented the development of hypertension. DS treatment resulted in an increased RSNA in MAT+/+ mice of about 2-fold (150 ± 3 spikes/sec) compared to sham-treated mice (65 ± 6 spikes/sec). Interestingly, RSNA was significantly reduced in MAT-/-DS mice, supporting the role of microglial ADAM17 in increasing sympathetic activity to the kidney. In DS hypertension, fibrosis is a prominent feature, secondary to increased sympathetic activity, contributing to end-organ dysfunction. Masson trichrome’ s staining confirmed increased fibrosis in the kidney and heart of MAT+/+DS mice which is significantly decreased in MAT-/- DS and MAT+/+ group. Altogether these data support the hypothesis that ADAM17 plays a crucial role in microglia by contributing to enhanced sympathetic activity and associated fibrosis during the development of salt-sensitive hypertension. This abstract was presented at the American Physiology Summit 2026 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.
Mohan et al. (Fri,) conducted a other in Salt-sensitive hypertension. Selective deletion of ADAM17 in microglia (MAT-/-) vs. Littermate controls (MAT+/+) was evaluated on Mean arterial blood pressure (mmHg). Selective deletion of ADAM17 in microglia prevented the development of salt-sensitive hypertension, significantly decreasing mean arterial blood pressure (92 vs 109 mmHg) and sympathetic activity.