ADAM17 on glutamatergic neurons inhibits GABAergic signaling in a salt‐sensitive hypertension model

Abstract

The brain plays an important role in modulating sympathetic drive to individual organs, leading to changes in cardiac output, vascular resistance and blood pressure regulation. Within the central nervous system, A Disintegrin And Metalloprotease 17 (ADAM17) impairs the compensatory activity of angiotensin converting enzyme type 2 (ACE2) through ectodomain shedding during hypertension. We previously observed that activation of neuronal ADAM17, especially in excitatory neurons, contributes to the development of neurogenic hypertension through promoting sympatho‐excitation. It was also revealed that ADAM17 located on glutamatergic neurons plays a supportive role in Ang‐II‐induced neuronal activation. To investigate the contributing mechanism, deoxycorticosterone (DOCA)‐salt (1mg/g body weight sc + 1% saline po for 3 weeks) or sham treatment was given to mice harboring ADAM17 knockdown in glutamatergic neurons (A17G) and their control littermates (C57Bl6/J male mice, 14–16 week‐old, n=10). At the end of the treatment, mice were sacrificed and their brains were collected. Expression levels of NMDA receptors (Grin1), AMPA receptors (GluR1), as well as GABAa receptors and Gad67 was assessed by QRT‐PCR. Among these genes, mRNA levels for Grin1, GluR1, and GABAa receptors were shown to be unaffected in the hypothalamus of either A17G mice or controls. However, mRNA level of Gad67, a critical enzyme that catalyzes the formation of GABA, was found to be significantly reduced in DOCA‐salt‐treated control mice, while it was significantly upregulated in the hypothalamus of DOCA‐salt‐treated A17G mice, implying that activation of ADAM17 in glutamatergic neurons might have a negative impact on GABAergic signaling. It was reported previously that neuro‐inflammation, especially microglia activation, can increase glutamate activity and decrease GABA synthesis as well as its release. Through CD11b labeling, we observed that less microglia was activated by DOCA‐salt treatment in the hypothalamus of A17G mice, compared to controls. Meanwhile, the markedly reduced interleukin‐6 (IL‐6) level in the hypothalamus also suggested that DOCA‐salt‐induced neuro‐inflammation was blunted in mice lacking ADAM17 in glutamatergic neurons. In addition, the distribution of ADAM17 was also studied. Beyond glutamatergic neurons, assessment of ADAM17’s presence in other neuronal populations and brain regions revealed its expression in GABAergic neurons within the MnPO (median preoptic nucleus), PVN and BNST (bed nucleus of the stria terminalis). Although the mechanism still needs to be verified, ADAM17‐mediated shedding in glutamatergic neurons seems to blunt GABAergic inhibitory activity. This may support the increase of glutamatergic neuronal excitability and sympatho‐excitation during DOCA‐salt hypertension.Support or Funding InformationVeterans Affairs Merit Award (BX004294), National Institutes of Health (HL093178 and COBRE P30GM106392) and LSUHSC‐NO Research Enhancement Program.