AT1R dysregulation is crucial in the hypertension of human GRK4γ A142V transgenic mice

The renin‐angiotensin system (RAS), via the AT1 receptor (AT1R), plays a critical role in the control of blood pressure (BP) by regulating peripheral resistance and sodium balance. Dopamine, via several dopamine receptor subtypes (e.g., D1R), counter regulates the RAS, including the AT1R. Recent studies have revealed an important role of G protein‐coupled receptor kinases (GRKs) in BP control by regulating several G protein‐coupled receptors, including the AT1R and D1R. Polymorphisms of GRK subtype 4 (GRK4), by themselves or via their interaction with genes regulating the RAS, are associated with essential hypertension. We now report that human GKR4γ A142V transgenic mice (A142V‐Tg) relative to hGRK4γ wild‐type transgenic mice (WT‐Tg) are hypertensive and have increased expression of AT1R, associated with increased AT1R promoter activity. A142V‐Tg mice have increased BP response to angiotensin II infusion and AT1R blockade. Moreover, A142V‐Tg mice that are deficient of AT1R have normal BP. This is the first report showing a molecular mechanism for the regulation of the AT1R gene that affects BP control. The GRK4 gene by regulating several genes involved in BP control may explain the "apparent" polygenic nature of essential hypertension.