主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Hypertension is common and in the majority of cases its cause remains unknown. Recent interest has focused on the role of macrophages (M Φ) in blood pressure (BP) regulation. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor mediating its effects through two receptors - the endothelin-A receptor (ETA) and endothelin-B (ETB) receptor. The ET B receptor has a specific role in ET-1 clearance. We investigated the role of the M Φ ETB receptor in a model of angiotensin II (Ang II)-mediated end-organ damage.
MΦ ETB receptor deficient mice (LysMETB-/-) and controls were exposed to Ang II infusion for 6 weeks under a high salt diet. We assessed BP via telemetry, cardiac structure and function and endothelial function by Doppler ultrasound, end-organ injury and plasma and urine ET-1.
At baseline, components of BP did not differ between groups and increased similarly with Ang II. Whereas after 6 weeks of Ang II LysMETB-/- and controls had similar left ventricular hypertrophy and cardiac insufficiency, endothelial function was better in LysMETB-/- at both baseline and after Ang II (% dilation of basilar artery in response to CO2, LysMETB-/- vs. controls: baseline: 20 vs.11%, p<0.01; at 6 weeks: 11 vs.0%, p<0.01). Baseline renal function and proteinuria did not differ between groups. After Ang II, LysMETB-/-showed similar renal function compared to controls but less proteinuria (urine albumin:creat, mg/mmol: 208 ± 10 vs. 530 ± 25, p<0.01), glomerulosclerosis (34 ± 2 vs. 61 ± 4%, p<0.001), and fewer renal MΦ compared to controls (F4/80 staining per high power field, LysMETB-/- vs. controls: 1.1 ± 0.7 vs.3.2 ± 0.5%, p=0.02), although similar levels of CD3+ T cells. Plasma ET-1 was no different at baseline but increased more in LysMETB-/- with Ang II (LysMETB-/- vs. controls after 6 weeks Ang II: 3.7 ± 0.7 vs.1.4 ± 0.2 pg/ml, p=0.03). Urine ET-1 was similar baseline and 6 weeks.
Deletion of the MΦ ETBR is associated with a blunting of the effects of systemic Ang II infusion as reflected by less endothelial dysfunction, reduced inflammation and end-organ damage. The mechanisms for these effects are the focus of ongoing research.
