Deletion of ADAM17 on microglia attenuates salt-sensitive hypertension

Previous work from our group identified ADAM17-mediated shedding as a major mechanism responsible for ACE2 shedding, thus impairing ACE2 compensatory activity and contributing to the development of salt sensitive hypertension. While microglia have been shown to contribute to salt sensitive hypertension, the mechanisms responsible are unknown. Accordingly, we hypothesize that ADAM17 promotes microglia priming, sympatho-excitation and neuro-inflammation in salt sensitive hypertension, and thus targeting ADAM17 or its maturation, via iRhom2, provides a multi-pronged strategy to normalize BP. Here, we aimed to evaluate whether deletion of ADAM17 on microglia attenuates hypertension. Uninephrectomized male and female mice (14–16-week-old, n=10/group) with selective deletion of ADAM17 in microglia (Cx3CR1-ADAM17tom) or with global deletion of iRhom2 (iRhom2-KO) and littermate controls (Cx3CR1-Cretom) mice were used to monitor blood pressure (BP telemetry, DSI) at baseline and following the initiation of salt sensitive hypertension (DOCA 1mg/g body weight sc + 1% saline po for 3 weeks). Following the establishment of hypertension (7 days post DOCA implantation) mice were injected with tamoxifen (200 nl ICV) and monitored for 2 more weeks. At the end of the treatment, mice were euthanized, and their brains were collected. Baseline mean arterial pressure (MAP) was not different in Cx3CR1-ADAM17tom, iRhom2-KO compared to controls (102±1, 106±1 and 104±1 mmHg, respectively). Surprisingly, all mice developed hypertension following DOCA implantation, including iRhom2 KO (Cx3CR1-ADAM17tom: 131±1, iRhom2 KO: 131±1, control: 126±1 mmHg, respectively. p<0.05). Interestingly, following tamoxifen injection Cx3CR1-ADAM17tom mice showed a blunted hypertension compared to the control group (MAP: 122±0.2 vs. 146±0.5 mmHg, one way ANOVA, p<0.05) suggesting that ADAM17 in microglia contributes to salt sensitive hypertension. In vitro, human microglia cells (iCell microglia — hIPSC) were shown to express lower ACE2 protein (0.03 ± 0.1 vs. 1.18 ± 0.3, Student’s t test, p<0.05) when exposed to Ang-II (100 ng) with a trend for ADAM17 upregulation (1.5 ± 0.3 vs. 1.1 ± 0.1, p<0.05). Together, our data suggest that overactivity of the renin-angiotensin system is associated with overexpression of ADAM17 in microglia and a simultaneous downregulation of ACE2. In addition, knockdown of ADAM17 specifically on microglia blunted the development of hypertension. We conclude that ADAM17 expression 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 is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.