Abstract 52: Human Grk4γ142v, Via Histone Deacetylase 1, Produces At1r-dependent Hypertension

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Abstract

Human gene variants account for only a small proportion of essential hypertension in humans and have not been shown to produce hypertension in transgenic mice. The association between hypertension and 11 allelic variants of 8 candidate genes in humans (n=1074) was studied. We also evaluated the response to angiotensin receptor blockers (ARBs) in humans (n=681) and transgenic mice generated to express the human wild-type G protein-coupled receptor kinase 4γ (hGRK4γWT) or the 142V allele (hGRK4γ142V). hGRK4γ variants (R65L, A142V, and A486V) were associated with essential hypertension; hGRK4γ142V, by itself, predicted the hypertensive phenotype (60% accuracy); hGRK4γ142V also interacted with GNB3 and PAI-1. Human hypertensive carriers of hGRK4γ142V (n=68) had a greater decrease in systolic blood pressure (SBP mm Hg, 19.36, vs. 14.58, P=0.001) in response to ARBs than non-carrier (n=135) hypertensives. hGRK4γWT transgenic mice (anesthetized, n=42; conscious [n=12, day=118±0.8, night=131±1]) were normotensive while hGRK4γ142V mice (anesthetized, n=54;conscious [n=12, day=128±2, night=148±3]) had hypertension, increased renal AT1R expression due to decreased histone deacetylase 1 (HDAC1) activity, a greater pressor response to angiotensin II (1000 ng/kg/minX30’)(n=6-9/group, WT=Δ+14±4%, 142V=Δ+26±3%), and a greater fall in SBP with candesartan (2mg/kg/dayX4d) (n=7/group, WT=Δ-5±2%,142V=Δ-29±3%); deletion of Agtr1a normalized the high BP of hGRK4γ142V mice (n=5-13/group). To determine the role of renal HDAC1 on BP, HDAC1 was silenced with HDAC-siRNA. Renal-specific HDAC1, but not HDAC2, silencing increased SBP (HDAC1-siRNA=112±5; mock=91±2; P<0.004, n=5/group). The BP response to ARBs was greater in HDAC1-siRNA- than mock-treated mice. These studies show that hGRK4γ142V is associated with human essential hypertension, produces AT1R-sensitive hypertension in hGRK4γ142V transgenic mice, and predicts a greater decrease in BP in response to ARBs in humans with essential hypertension and hGRK4γ142V transgenic mice. This is the first demonstration of a concordance between rodents and humans for genetics, signaling pathway, and pharmacogenetics of essential hypertension.

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