Abstract
Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.
Highlights
Early in vivo proximal tubule micropuncture experiments in rats [93,94] and in vitro isolated proximal tubule perfusion studies in rabbits or rats [78,95] established important milestones by demonstrating direct biphasic effects of angiotensin II (Ang II) on proximal tubule Na+ transport function. This was followed by subsequent loss or gain of AT1 (AT1a ) receptor function studies in mice using the kidney-cross transplantation between wild-type and Agtr1a-/- mice, firmly confirming the critical role of kidney AT1 (AT1a ) receptors in blood pressure control and hypertension [10,96]
These studies have not be able to determine the direct role of intratubular Ang II and AT1 (AT1a ) receptors in the proximal tubules in blood pressure control and Ang II-induced hypertension
This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss or gain of the function [12–14,16,27,28,97]. These new studies have consistently demonstrated that deletion of AT1 (AT1a ) receptors [12,15,16] or its direct downstream target, Na+/H+ exchanger 3 (NHE3), selectively in the proximal tubules of the kidney [13,14] lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a ) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure [71,106,107]
Summary
Several classes of drugs are currently available to treat hypertension, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II (Ang II) receptor blockers (ARBs), calcium channel inhibitors, β-blockers, and loop diuretics These antihypertensive drugs act to either inhibit the renin–angiotensin system (RAS), cause blood vessel vasodilatation, induce natriuresis and diuresis, or suppress sympathetic nerve activity [4–7]. A significant increase in arterial blood pressure is expected to trigger the pressure-natriuresis response that, in turn, alters interstitial hydrostatic pressure, proximal tubule Na+ transport, and renal medullary blood flow to induce diuresis and natriuresis responses. Recent studies suggest that the intratubular RAS, especially Ang II via activation of AT1 (AT1a ) receptors in the proximal tubules of the kidney, plays a key role in basal blood pressure control and the development of Ang II-induced hypertension by regulating proximal tubule Na+ reabsorption and the pressure-natriuresis response [9–11]. This new knowledge improves our understanding of the renal mechanisms of blood pressure regulation as well as Ang II-induced hypertension and suggests that both AT1a receptors and NHE3 may be potential therapeutic targets in treating hypertension in humans
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