Abstract P210: Mir-204 In Endothelial Cells Contributes To The Development Of Hypertension

Global knockout of microRNA miR-204 leads to significant attenuation of hypertension in mice treated with uninephrectomy, angiotensin II (AngII), and a high-salt diet. We hypothesize that miR-204 in endothelial cells (EC) contributes to hypertension. We developed Mir204 fl/fl mice and crossed them with VE-Cadherin-Cre mice. The loss of miR-204 was confirmed in isolated endothelial cells (1 ± 0.15, 0.41 and 0.13 ± 0.05, fold in EC- Mir204 +/+ , EC- Mir204 +/- , and EC- Mir204 -/- mice, respectively; n=4, 1, and 4). AngII and 4% NaCl diet increased systolic blood pressure (SBP) by up to 40-50 mmHg in both male and female EC- Mir204 +/- and WT littermates (n=11 and 17). The SBP was significantly decreased by 20-30 mmHg in EC- Mir204 -/- mice (P < 0.05, n=10). Vascular function was assessed by pressure myograph in basilar artery following the Ang II and 4% NaCl diet treatment. In EC- Mir204 -/- male mice, the wall thickness (21.5 ± 0.1 vs 30 ± 3.1μm, n=7 and 2) and media/lumen ratio (0.2 ± 0.01 vs 0.51 ± 0.09, n=7 and 2) was significantly reduced compared with EC- Mir204 +/+ mice. Endothelial-dependent vasodilation (response to Ach) was lost in EC- Mir204 +/+ mice but largely preserved in EC- Mir204 -/- mice (P= 0.007). Renal interstitial fibrosis was not influenced by the miR-204 KO in endothelial cells (Cortex: 0.27 ± 0.04, 0.18 ± 0.01 %; Outer medulla: 0.18 ± 0.05, 0.19 ± 0.05 % in EC- Mir204 +/+ and EC- Mir204 -/- male mice, respectively; n=3 and 2). Urinary albumin excretion was increased during the two-week treatment. However, the albuminuria was not significantly affected by the knockout of miR-204 in endothelial cells (2.65 ± 1.13, 3.41 ± 0.86, and 2.86 ± 0.85 mg/24h in EC- Mir204 +/+ , EC- Mir204 +/- , and EC- Mir204 -/- mice, respectively; n=9, 11 and 6). Glomerular filtration rate did not differ among the three groups at baseline or study termination (Baseline: 188.3 ± 30.1, 223.1 ± 34.9, and 185.3 ± 21.3 μl/min, n=4, 2 and 5; Termination: 203.8 ± 22.1, 150.7 ± 30.3, and 193.9 ± 42.5 μl/min, n=6, 2 and 5 in EC- Mir204 +/+ , EC- Mir204 +/- , and EC- Mir204 -/- mice, respectively). The findings suggest that miR-204 in endothelial cells plays an important role in the development of hypertension associated with impaired endothelial-dependent vasodilation and vascular remodeling.