Deletion of the angiotensin II type 1 receptor–associated protein enhances renal sodium reabsorption and exacerbates angiotensin II–mediated hypertension (original) (raw)
Related papers
Role of AT1 receptor-mediated salt retention in angiotensin II-dependent hypertension
AJP: Renal Physiology, 2011
Activation of type 1 angiotensin II (AT1) receptors in the kidney promotes blood pressure elevation and target organ damage, but whether renal AT1 receptors influence the level of hypertension by stimulating sodium retention or by raising systemic vascular resistance has not been established. In the current studies, we used a kidney cross-transplantation strategy to determine whether increased sodium reabsorption by AT1 receptors in the kidney mediates the chronic hypertensive response to angiotensin II. We found this to be true. In addition, we also identified a second, nontrivial component of blood pressure elevation induced by activation of renal AT1 receptors that is sodium-independent. As the kidney has the capacity to limit the transmission of elevated systemic blood pressure into the renal microcirculation, prior studies struggled to clearly discriminate the relative contributions of blood pressure elevation vs. activation of AT1 receptors to hypertensive kidney injury. In ou...
Hypertension, 2013
M ost physiological actions of angiotensin (Ang) II are mediated by its binding to the Ang II type 1 receptors (AT 1 R). These include, but are not limited to, vasoconstriction, increased renal sodium and water reabsorption, as well as the stimulation of aldosterone release, thirst, vasopressin secretion, and cell growth. Not surprisingly, the biochemistry of the AT 1 R has been a subject of intense research for >30 years. These studies revealed that the cytoplasmic tail of the AT 1 R is an important site for several protein-to-protein interactions, phosphorylation, and thereby the regulation of receptor signaling, desensitization, and endocytosis. 1 Accordingly, considerable efforts have been made to identify and to study molecules with affinity to this region; one of such molecules is the angiotensin receptor-associated protein (ATRAP).
Hypertension, 2013
We have previously shown that angiotensin II type 1 receptor-associated protein (ATRAP/ Agtrap ) interacts with the angiotensin II type 1 receptor and promotes constitutive internalization of the receptor so as to inhibit the pathological activation of its downstream signaling but preserve baseline physiological signaling activity. The present study was designed to investigate the role of renal ATRAP in angiotensin II–dependent hypertension. We generated transgenic mice dominantly expressing ATRAP in the renal tubules, including renal distal tubules. The renal ATRAP transgenic mice exhibited no significant change in blood pressure at baseline on normal salt diet. However, in the renal ATRAP transgenic mice compared with wild-type mice, the following took place: (1) the development of high blood pressure in response to angiotensin II infusion was significantly suppressed based on radiotelemetry, (2) the extent of daily positive sodium balance was significantly reduced during angioten...
Nephron Experimental Nephrology, 2012
Epithelial sodium channels (ENaC) are ion transporters in the aldosterone-sensitive distal nephron that play an important role in sodium reabsorption in the terminal nephron. Our study of inbred C57Bl6/J mice given a high-sodium diet showed increased ENaC expression accompanied by tubular renin activation on qRT-PCR of laser-captured tubule specimens and Western blotting of membrane proteins, despite inhibition of aldosterone. Treatment with an angiotensin-converting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) effectively lowered blood pressure. In addition to lowering blood pressure, ACEI and ARB inhibition downregulated ENaC and renin expression in renal tubules. These effects would act to suppress sodium reabsorption via ENaC and normalize molecular mechanisms that elevate blood pressure in response to increased salt intake.
Journal of the American Society of Nephrology : JASN, 2015
Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely ...
Journal of Korean medical science, 2005
We aimed to examine the effects of angiotensin II AT(1) receptor blocker on the expression of major renal sodium transporters and aquaporin-2 (AQP2) in rats with chronic renal failure (CRF). During 2 wks after 5/6 nephrectomy or sham operation, both CRF rats (n=10) and sham-operated control rats (n=7) received a fixed amount of low sodium diet and had free access to water. CRF rats (n=10) were divided into two groups which were either candesartan-treated (CRF-C, n=4) or vehicle-treated (CRF-V, n=6). Both CRF-C and CRF-V demonstrated azotemia, decreased GFR, polyuria, and decreased urine osmolality compared with sham-operated rats. When compared with CRF-V, CRF-C was associated with significantly higher BUN levels and lower remnant kidney weight. Semiquantitative immunoblotting demonstrated decreased AQP2 expression in both CRF-C (54% of control levels) and CRF-V (57%), whereas BSC-1 expression was increased in both CRF groups. Particularly, CRF-C was associated with higher BSC-1 exp...
Journal of Clinical Investigation, 1997
Studies determined the effects of chronic changes in sodium diet on the expression, regulation, and function of different angiotensin II (ANG II) receptor subtypes in renal resistance vessels. Rats were fed low-or high-sodium diets for 3 wk before study. Receptor function was assessed in vivo by measuring transient renal blood flow responses to bolus injections of ANG II (2 ng) into the renal artery. ANG II produced less pronounced renal vasoconstriction in rats fed a low-compared with high-sodium diet (16% vs. 56% decrease in renal blood flow, P Ͻ 0.001). After acute blockade of ANG II formation by iv enalaprilat injection in sodiumrestricted animals, ANG II produced a 40% decrease in renal blood flow, a level between untreated dietary groups and less than high salt diet. Intrarenal administration of angiotensin II receptor type 1 (AT 1) receptor antagonists losartan or EXP-3174 simultaneously with ANG II caused dosedependent inhibition of ANG II responses. Based on maximum vasoconstriction normalized to 100% ANG II effect in each group, AT 1 receptor antagonists produced the same degree of blockade in all groups, with an apparent maximum of 80-90%. In contrast, similar doses of the angiotensin II receptor type 2 (AT 2) receptor ligand CGP-42112 had only a weak inhibitory effect. In vitro equilibrium-saturation 125 Chronic changes in sodium intake caused parallel regulation of expression and amount of receptor protein of the two AT 1 receptor genes that modulate receptor function and altered reactivity of renal vessels to ANG II.
AT1A Angiotensin Receptors in the Renal Proximal Tubule Regulate Blood Pressure
Cell Metabolism, 2011
Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and non-redundant role in determining the level of BP. Abrogation of AT 1 angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension.
Regulation by sodium intake of type 1 angiotensin II receptor mRNAs in the kidney of Sabra rats
Journal of Hypertension, 2000
Objective To study the relationship between the sensitivity to sodium content of the diet in terms of development of hypertension and the regulation of the expression of type 1 angiotensin II receptor subtypes by such a diet. Methods The expression of angiotensin II receptor subtype (AT 1A and AT 1B) mRNAs was studied by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the four zones of the kidneys of Sabra rats, sensitive or resistant to DOCA salt-induced hypertension (SBH/y and SBN/y, respectively). Rats were fed a high (8%) or normal (0.4%) NaCl diet. As vasopressin is known to be elevated in SBH/y rats and to be involved in DOCA-salt hypertension, we studied an additional group of SBH/y rats, fed a high sodium diet, enriched in water. Results With the absence of DOCA, SBH/y rats did not develop hypertension. The high sodium diet induced a greater fall in the plasma renin activity in the SBH/y (295%) than in the SBN/y (263%). In the cortex (C) and inner stripe (IS), the high sodium diet decreased AT 1A and AT 1B mRNAs in SBH/y and SBN/y, with a higher magnitude for SBH/y, than for SBN/y (C, 228 versus 220% ; IS, 242 versus 220%). The addition of water to the high sodium diet lessened the effect of sodium in the C and IS, although the plasma renin activity (PRA) was not altered. Conclusion A high sodium diet signi®cantly decreases both AT 1A and AT 1B gene expression in two speci®c zones of the rat kidney containing the target cells of angiotensin II (C and IS). This down-regulation is organ-speci®c since it was observed in the kidney and adrenals, but not in the liver. Finally, SBH/y and SBN/y rats differ in the basal level of AT 1 mRNA expression in the IS, and in the ability to modulate AT 1 mRNA level under sodium intake.
Compensatory up-regulation of angiotensin II subtype 1 receptors in αENaC knockout heterozygous mice
Kidney International, 2001
Compensatory up-regulation of angiotensin II subtype 1 receplial sodium reabsorption in the distal nephron, where tors in ␣ENaC knockout heterozygous mice. the fine regulation of sodium excretion occurs [1]. This Background. In mice, a partial loss of function of the epithechannel consists of three homologous subunits (␣, , and lial sodium channel (ENaC), which regulates sodium excretion ␥ENaC), which have been cloned in different species, in the distal nephron, causes pseudohypoaldosteronism, a saltincluding humans [2-4]. Using the knockout approach, wasting syndrome. The purpose of the present experiments was to examine how ␣ENaC knockout heterozygous (ϩ/Ϫ) inactivation of the gene coding for the ␣ subunit of ENaC mice, which have only one allele of the gene encoding for the has led to perinatal lethality because sodium reabsorp-␣ subunit of ENaC, control their blood pressure (BP) and tion was completely abolished in airway epithelia [5]. sodium balance.