Microglia morphology and function in salt sensitive hypertension depends on ACE2 expression

ACE2 plays a compensatory role in hypertension (HTN) and other cardiovascular diseases (CVD), but its expression is typically reduced in chronic hypertensive states. Microglia, the resident immune cells of the brain, contribute to neuroinflammation and HTN by releasing proinflammatory cytokines such as TNF-α and IL-6. Our recent observations indicate that ACE2 is expressed on microglia; however, its functional role in these cells remains unknown. This suggests a potential role for ACE2 in modulating microglial activation and cytokine secretion. Our aim is to understand the role of ACE2 in microglia activation in salt-sensitive hypertension. For that purpose, a new mouse model (MA-) amenable for selective deletion of ACE2 in microglia was developed. Uni-nephrectomized male mice (14–16-week-old) with selective deletion of ACE2 in microglia (MA-) or littermate controls (MA0) were used to monitor blood pressure (BP telemetry, DSI) at baseline and following injection with tamoxifen (400 nl ICV) to initiate ACE2 deletion in microglia. One week following baseline BP recording, mice received a deoxycorticosterone acetate pellet subcutaneously (DOCA, 50 mg) plus 1% salt in drinking water (DS). At the end of the treatment, mice were euthanized, and their brains were collected. Baseline mean arterial pressure (MAP) was not different between groups (MA0: 103 ±4, vs MA-: 106 ±1 mmHg, respectively) and all mice developed hypertension following DOCA implantation, (MAP: 145 ±5 mmHg). Interestingly, in the 2nd week of DOCA treatment, MA- mice showed a trend to increased blood pressure compared to the MA0 group suggesting that ACE2 in microglia might contribute to salt sensitive hypertension. We also observed changes in microglia morphology. Compared to DS controls, MA0+DS microglia exhibited a significant decrease in the mean length of the longest branch (P< 0.005). Furthermore, microglial density and circularity values were significantly decreased in the MA-DS group (P < 0.001), indicating that microglia in the hypothalamus were more compact and rounder. Interestingly, MA-DS mice showed an increased level of proinflammatory cytokines and chemokines in the hypothalamus, including, IL-6 (MA-+DS: 7 ±1, MA0 +DS: 1.5±0.2 vs. MA0: 0.3±0.1 pg/mL), MCP-1 (MA-+DS: 338.2 ±5, MA0 +DS: 153.7 ±10 vs. MA0: 61 ±14 pg/mL) and TNF-α (MA-+DS: 6 ±2, MA0 +DS: 3 ±0.3 vs. MA0: 1.1 ±0.2 pg/mL) respectively. Together, our data suggests that conditional deletion of ACE2 enhances the activation of microglia and increases pro-inflammatory cytokines and chemokines expression in hypertension. Overall, our data supports a pivotal role for microglial ACE2 in regulating salt-sensitive hypertension and the associated inflammation. 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.