Abstract
Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.
Highlights
Primary hypertension (HT) affects approximately 48% of the US adult population and constitutes a major risk factor for stroke, myocardial infarction, heart failure, and end-stage kidney disease [1,2,3]
Do selective renal proximal tubule cells (RPTCs) Ang II type-2 receptor (AT2R)-null mice have reduced baseline Na+ excretion, and do they have reduced natriuretic responses compared to wild type (WT) mice in response to Na+ loading? Do selective RPTC AT2R-null mice have defective pressure-natriuresis compared to WT? If so, what cellular mechanisms mediate these responses? Does selective RPTC AT2R deletion cause enough Na+ retention to increase blood pressure (BP) and/or lead to hypertension?
Chronic C-21-induced AT2R activation initiated and sustained AT2R translocation to RPTC apical plasma membranes (APMs) [40]. These results suggest that renal AT2R activation can surmount Na+ retention under pathological circumstances and may be an appropriate target for pharmacological stimulation of natriuresis and consequent lowering of BP when the renin-angiotensin system (RAS) is activated
Summary
Primary (essential) hypertension (HT) affects approximately 48% of the US adult population and constitutes a major risk factor for stroke, myocardial infarction, heart failure, and end-stage kidney disease [1,2,3]. The main RAS effector peptide angiotensin II (Ang II) acts at two major receptors, the Ang II type-1 receptor (AT1R) inducing renal Na+ reabsorption and increasing BP and the Ang II type-2 receptor (AT2R) which generally opposes AT1R actions. NA, non-applicable; -, experiment not been carried out; AT1R, angiotensin type-1 receptor; AT2R, angiotensin type-2 receptor; NO, nitric oxide; cGMP, cyclic GMP; PP2A, protein phosphatase 2A
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