Knock-Down of Adam17 in Glutamatergic or Pre-Autonomic Neurons Attenuates Development of Neurogenic Hypertension

Rationale and objectivesWe have previously reported that DOCA‐salt‐induced neurogenic hypertension is associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) activity in the hypothalamus. Blocking Angiotensin‐II type 1 receptors or silencing ADAM17 in the CNS prevented hypertension. Since ADAM17 is known to be expressed on different cell types in several brain regions and can be activated in multiple ways, we generated several specific knockout mice targeting ADAM17 in neurons, astrocytes and microglia. In one of these models, we tested the hypothesis that glutamatergic neurons expressing ADAM17 mediate ACE2 shedding from the cell membrane in neurogenic hypertension. Secondly, through selective knock‐down of ADAM17 in Sim1‐positive neurons we examined its role in pre‐autonomic neurons.MethodsPrimary neuronal cultures were used to substantiate glutamate's role in up‐regulating ADAM17 activity. In vivo, ADAM17 knock‐down mice (ADAM17 floxed crossed with either Vesicular Glutamate Transporter 2 ‐ cre or Sim1 – cre recombinase mice), and control littermates were implanted with telemetry probes for continuous recording of blood pressure (BP) and heart rate (HR) (N = 26 control; N = 3/group experimental). After baseline data were collected the mice underwent DOCA‐salt treatment (DOCA 1 mg/g body weight sc + 1% saline po) for 18–20 days.ResultsPrimary neurons exposed to glutamate showed increased expression of ADAM17 activity on the cell membrane (24.5±5%). Glutamatergic ADAM17 knock‐down animals, Sim1 ADAM17 knock‐down animals, and their control littermates showed increased BP after DOCA‐salt treatment (Control: +30 ±3 mmHg; ADAM17fl/flvGlut2: +10 ±4 mmHg; ADAM17fl/flSim1: +21.4 ±5). Importantly, mean arterial pressure and HR were significantly lower in mice with ADAM17 knocked‐down from glutamatergic neurons or Sim1 neurons after DOCA‐salt treatment compared to the controls (p<0.01 for all comparisons).ConclusionsADAM17 expression on glutamatergic neurons or Sim1 positive neurons does not influence BP and HR during normal resting conditions. However, this is the first evidence showing that these neuronal populations of ADAM17 positive cells are playing a critical role in mediating hypertension. Under DOCA‐salt‐induced neurogenic hypertension BP and HR both increase via pathways involving glutamatergic and Sim1 neurons with ADAM17.Support or Funding InformationNIH: HL093178 and GM106392; AHA: 12EIA8030004