Local and Downstream Actions of Proximal Tubule Angiotensin II Signaling on Sodium Transporters in the Mouse Nephron

2021 ◽  
Author(s):  
Jonathan William Nelson ◽  
Alicia A. McDonough ◽  
Zhidan Xiang ◽  
Donna L. Ralph ◽  
Joshua A Robertson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Sodium Reabsorption ◽  
Electrolyte Balance ◽  
Sodium Transporters ◽  
Lower Abundance ◽  
Angiotensin Ii Signaling ◽  
Distinct Cell

The renal nephron consists of a series of distinct cell types which function in concert to maintain fluid and electrolyte balance and blood pressure. The renin angiotensin system (RAS) is central to sodium and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered sodium and volume, impacts solute transport throughout the nephron. We hypothesized that proximal tubule (PT) RAS disruption would not only depress PT sodium transporters, but also impact downstream Na+ transporters. Utilizing a mouse model in which the type 1a angiotensin receptor (AT1aR) is deleted specifically within the PT (AT1aR PTKO), we profiled the abundance of sodium transporters, channels, and claudins along the nephron. Absence of PT AT1aR signaling was associated with lower abundance of PT transporters (NHE3, NBCe2 and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated NKCC2, medullary Na,K-ATPase, phosphorylated NCC and claudin 7) versus controls. However, transport activities of NKCC2 and NCC (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on sodium reabsorption in PT at baseline and the associated influence on downstream Na+ transporters, highlighting the ability of the nephron to integrate sodium transport along the nephron to maintain homeostasis.

scholarly journals Short-term nonpressor angiotensin II infusion stimulates sodium transporters in proximal tubule and distal nephron

2015 ◽  
Vol 3 (9) ◽  
pp. e12496 ◽  
Author(s):  
Mien T. X. Nguyen ◽  
Jiyang Han ◽  
Donna L. Ralph ◽  
Luciana C. Veiras ◽  
Alicia A. McDonough
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Distal Nephron ◽  
Short Term ◽  
Sodium Transporters

Androgens augment proximal tubule transport

2004 ◽  
Vol 287 (3) ◽  
pp. F452-F459 ◽  
Author(s):  
Albert Quan ◽  
Sumana Chakravarty ◽  
Jian-Kang Chen ◽  
Jian-Chun Chen ◽  
Samer Loleh ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Specific Binding ◽  
Extracellular Volume ◽  
Renin Angiotensin System ◽  
Angiotensin Receptors ◽  
Sprague Dawley ◽  
Angiotensin System ◽  
Renin Angiotensin

The proximal tubule contains an autonomous renin-angiotensin system that regulates transport independently of circulating angiotensin II. Androgens are known to increase expression of angiotensinogen, but the effect of androgens on proximal tubule transport is unknown. In this in vivo microperfusion study, we examined the effect of androgens on proximal tubule transport. The volume reabsorptive rate in Sprague-Dawley rats given dihydrotestosterone (DHT) injections was significantly higher than in control rats given vehicle injections (4.57 ± 0.31 vs. 3.31 ± 0.23 nl·min−1·mm−1, P < 0.01). Luminally perfusing with either enalaprilat (10−4 M) to inhibit production of angiotensin II or losartan (10−8 M) to block the angiotensin receptor decreased the proximal tubule volume reabsorptive rate in DHT-treated rats to a significantly greater degree than in control vehicle-injected rats. The renal expression of angiotensinogen was shown to be higher in the DHT-treated animals, using Northern blot analysis. The expression of angiotensin receptors, determined by specific binding of angiotensin II, was not different in the two groups of animals. Brush-border membrane protein abundance of the Na/H exchanger, a membrane transport protein under angiotensin II regulation, was also higher in DHT-treated rats vs. control rats. Rats that received DHT had higher blood pressures than the control rats but had no change in their glomerular filtration rate. In addition, serum angiotensin II levels were lower in DHT-treated vs. control rats. These results suggest that androgens may directly upregulate the proximal tubule renin-angiotensin system, increase the volume reabsorptive rate, and thereby increase extracellular volume and blood pressure and secondarily decrease serum angiotensin II levels.

Natriuretic response to renal interstitial hydrostatic pressure during angiotensin II blockade

1994 ◽  
Vol 266 (1) ◽  
pp. F117-F119 ◽  
Author(s):  
J. A. Haas ◽  
J. C. Lockhart ◽  
T. S. Larson ◽  
T. Henrikson ◽  
F. G. Knox
Keyword(s):  
Angiotensin Ii ◽  
Hydrostatic Pressure ◽  
Sodium Excretion ◽  
Renin Angiotensin System ◽  
Urinary Sodium Excretion ◽  
Treated Group ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Angiotensin System ◽  
Before And After

Increases in renal interstitial hydrostatic pressure (RIHP) increase urinary sodium excretion (UNaV). Experimentally increasing RIHP by direct renal interstitial volume expansion (DRIVE) has been shown to decrease proximal tubule sodium reabsorption. The purpose of the present study was to investigate whether the renin-angiotensin system modulates the natriuretic response to DRIVE. Unilateral nephrectomy and implantation of two polyethylene matrices were performed 3 wk before the acute experiment. Fractional sodium excretion (FENa), RIHP, and glomerular filtration rate (GFR) were measured before and after DRIVE in control rats (n = 9) and in rats receiving the angiotensin II (ANG II) receptor antagonist, losartan potassium (10 mg/kg i.v.; n = 10). DRIVE was achieved by infusing 100 microliters of 2.5% albumin solution directly into the renal interstitium. GFR remained unchanged by DRIVE in both groups. In control animals, DRIVE significantly increased both RIHP (delta 3.8 +/- 0.5 mmHg) and FENa (delta 0.92 +/- 0.19%). In the losartan-treated group, RIHP (delta 2.8 +/- 0.4 mmHg) and FENa (delta 1.93 +/- 0.41%) also significantly increased. The natriuretic response to DRIVE was significantly enhanced during ANG II receptor blockade compared with control animals (delta UNaV/delta RIHP = 2.01 +/- 0.67 vs. 0.44 +/- 0.17 mu eq.min-1 x mmHg-1, respectively; P < 0.05). These results suggest that the blockade of angiotensin enhances the natriuretic response to increased RIHP during DRIVE.

Renal nerve stimulation augments effect of intraluminal angiotensin II on proximal tubule transport

2002 ◽  
Vol 282 (6) ◽  
pp. F1043-F1048 ◽  
Author(s):  
Albert Quan ◽  
Michel Baum
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Nerve Stimulation ◽  
Filtration Rate ◽  
Renin Angiotensin System ◽  
Renal Nerves ◽  
Renal Nerve ◽  
Angiotensin System ◽  
Renal Nerve Stimulation

The proximal tubule synthesizes and secretes angiotensin II into the lumen, where it regulates transport. Renal denervation abolishes the effect of angiotensin II on proximal tubule transport. Using in vivo microperfusion, we examined whether renal nerve stimulation modulates the effect of angiotensin II on transport. The effect of angiotensin II was assessed by measuring the decrease in volume reabsorption with the addition of 10−4M luminal enalaprilat. Luminal enalaprilat did not alter volume reabsorption (2.80 ± 0.18 vs. 2.34 ± 0.14 nl · mm−1 · min−1). However, with renal nerve stimulation, enalaprilat decreased volume reabsorption (3.45 ± 0.22 vs. 1.67 ± 0.20 nl · mm−1 · min−1, P < 0.0005). The absolute and percent decrements in volume reabsorption with luminal enalaprilat were higher with renal nerve stimulation than with native innervation (1.78 ± 0.19 vs. 0.46 ± 0.23 nl · mm−1 · min−1, P < 0.02, and 51.8 ± 5.0 vs. 14.6 ± 7.4%, P < 0.05, respectively). Renal nerve stimulation did not alter the glomerular filtration rate or renal blood flow. Renal nerve stimulation augments the stimulatory effect of intraluminal angiotensin II. The sympathetic renal nerves modulate the proximal tubule renin-angiotensin system and thereby regulate proximal tubule transport.

scholarly journals Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3601-3614 ◽  
Author(s):  
Elias T. Zambidis ◽  
Tea Soon Park ◽  
Wayne Yu ◽  
Ada Tam ◽  
Michal Levine ◽  
...  
Keyword(s):  
Stem Cells ◽  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Embryoid Body ◽  
Embryonic Stem ◽  
Renin Angiotensin System ◽  
Converting Enzyme ◽  
Embryonic Tissues ◽  
Angiotensin Ii Signaling ◽  
Normal Human

We report that angiotensin-converting enzyme (ACE), a critical physiologic regulator of blood pressure, angiogenesis, and inflammation, is a novel marker for identifying hemangioblasts differentiating from human embryonic stem cells (hESC). We demonstrate that ACE+CD45−CD34+/− hemangioblasts are common yolk sac (YS)–like progenitors for not only endothelium but also both primitive and definitive human lymphohematopoietic cells. Thrombopoietin and basic fibroblast growth factor are identified as critical factors for the proliferation of human hemangioblasts. The developmental sequence of human embryoid body hematopoiesis is remarkably congruent to the timeline of normal human YS development, which occurs during weeks 2 to 6 of human gestation. Furthermore, ACE and the renin-angiotensin system (RAS) directly regulate hemangioblast expansion and differentiation via signaling through the angiotensin II receptors AGTR1 and AGTR2. ACE enzymatic activity is required for hemangioblast expansion, and differentiation toward either endothelium or multipotent hematopoietic progenitors is dramatically augmented after manipulation of angiotensin II signaling with either AGTR1- or AGTR2-specific inhibitors. The RAS can therefore be exploited to direct the hematopoietic or endothelial fate of hESC-derived hemangioblasts, thus providing novel opportunities for human tissue engineering. Moreover, the initial events of human hematoendotheliogenesis can be delineated in a manner previously impossible because of inaccessibility to early human embryonic tissues.

Angiotensin II mediates downregulation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction

2006 ◽  
Vol 291 (5) ◽  
pp. F1021-F1032 ◽  
Author(s):  
Anja M. Jensen ◽  
Chunling Li ◽  
Helle A. Praetorius ◽  
Rikke Nørregaard ◽  
Sebastian Frische ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Obstruction ◽  
Renin Angiotensin System ◽  
Urine Osmolality ◽  
Water Channels ◽  
Sodium Reabsorption ◽  
Sodium Transporters ◽  
Cox 2

The renin-angiotensin system is well known to be involved in the pathophysiological changes in renal function after obstruction of the ureter. Previously, we demonstrated that bilateral ureteral obstruction (BUO) is associated with dramatic changes in the expression of both renal sodium transporters and aquaporin water channels (AQPs). We now examined the effects of the AT1-receptor antagonist candesartan on the dysregulation of AQPs and key renal sodium transporters in rats subjected to 24-h BUO and followed 2 days after release of BUO (BUO-2R). Consistent with previous observations, BUO-2R resulted in a significantly decreased expression of AQP1, -2, and -3 compared with control rats. Concomitantly, the rats developed polyuria and reduced urine osmolality. Moreover, expression of the type 2 Na-phosphate cotransporter (NaPi-2) and type 1 bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) was markedly reduced, consistent with postobstructive natriuresis. Candesartan treatment from the onset of obstruction attenuated the reduction in GFR (3.1 ± 0.4 vs. 1.7 ± 0.3 ml·min−1·kg−1) and partially prevented the reduction in the expression of AQP2 (66 ± 21 vs. 13 ± 2%, n = 7; P < 0.05), NaPi-2 (84 ± 6 vs. 57 ± 10%, n = 7; P < 0.05), and NKCC2 (89 ± 12 vs. 46% ± 11, n = 7; P < 0.05). Consistent with this, candesartan treatment attenuated the increase in urine output (58 ± 4 vs. 97 ± 5 μl·min−1·kg−1, n = 7; P < 0.01) and the reduction in sodium reabsorption (433 ± 62 vs. 233 ± 45 μmol·min−1·kg−1, n = 7; P < 0.05) normally found in rats subjected to BUO. Moreover, candesartan treatment attenuated induction of cyclooxygenase 2 (COX-2) expression in the inner medulla, suggesting that COX-2 induction in response to obstruction is regulated by ANG II. In conclusion, candesartan prevents dysregulation of AQP2, sodium transporters, and development of polyuria seen in BUO. This strongly supports the view that candesartan protects kidney function in response to urinary tract obstruction.

Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease

2016 ◽  
Vol 130 (15) ◽  
pp. 1307-1326 ◽  
Author(s):  
Bryna S.M. Chow ◽  
Terri J. Allen
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Cellular Growth ◽  
Receptor Subtype ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Biological Responses

Angiotensin II (Ang II) is well-considered to be the principal effector of the renin–angiotensin system (RAS), which binds with strong affinity to the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptor subtype. However, activation of both receptors is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses. The haemodynamic and non-haemodynamic effects of Ang II, including its ability to regulate blood pressure, maintain water–electrolyte balance and promote vasoconstriction and cellular growth are well-documented to be mediated primarily by the AT1R. However, its biological and functional effects mediated through the AT2R subtype are still poorly understood. Recent studies have emphasized that activation of the AT2R regulates tissue and organ development and provides in certain context a potential counter-regulatory mechanism against AT1R-mediated actions. Thus, this review will focus on providing insights into the biological role of the AT2R, in particular its actions within the renal and cardiovascular system.

scholarly journals The Renin-Angiotensin System: A Key Role in SARS-CoV-2- Induced COVID-19

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6945
Author(s):  
George El-Arif ◽  
Antonella Farhat ◽  
Shaymaa Khazaal ◽  
Cédric Annweiler ◽  
Hervé Kovacic ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Organ Damage ◽  
World Health ◽  
Electrolyte Balance ◽  
Type I ◽  
Related Factors ◽  
Angiotensin System ◽  
Mortality And Morbidity ◽  
Renin Angiotensin

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin–angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)–angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

Abstract MP46: Mutagenesis Of PRR Cleavage Site In Mice Attenuates Angiotensin II-induced Hypertension And Suppresses Renin Expression

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Fei Wang ◽  
Yanting Chen ◽  
Chang-jiang Zou ◽  
Renfei Luo ◽  
Tianxin Yang
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
Cleavage Site ◽  
Collecting Duct ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Mouse Cell ◽  
Mrna Levels ◽  
Direct Role ◽  
Induced Hypertension

It is well demonstrated that activation of renal (pro)renin receptor (PRR) contributes to AngII-induced hypertension. Relatively, less is known about involvement of soluble PRR (sPRR), the extracellular domain of PRR, primarily generated by site-1 protease(S1P) and furin. Moreover, the relationship between PRR/sPRR and the renin-angiotensin system (RAS) has been debated. In the present study, we used CRISPR/Cas9 strategy to generate mice with mutagenesis of the overlapping cleavage site for both proteases in PRR (termed as PRR R279V/L282V ) to examine the phenotype during angiotensin II (AngII) infusion with particular emphasis on circulating and intrarenal renin status. PRR R279V/L282V mice exhibited a reduction of sPRR level in plasma by ~53% and in the kidney by ~82%, were fertile, and had no gross developmental abnormalities. At basal condition, PRR R279V/L282V mice had drastically suppressed renin levels from plasma (plasma total prorenin/renin content [ng/ml]: 9.3 ± 0.7 in PRR R279V/L282V mice vs. 12.8 ± 0.9 in WT mice, n = 5, p < 0.05), urine (urinary total prorenin/renin excretion [ng/24h]: 0.54 ± 0.11 in PRR R279V/L282V mice vs. 1.05 ± 0.15 in WT mice, n = 5, p < 0.05), and the kidney as compared to wild-type controls (WT). By telemetry, the hypertensive response of PRR R279V/L282V to AngII infusion (300 ng/min/kg) was blunted (MAP [mmHg] in Day 10: 125.9 ± 4.6 in PRR R279V/L282V mice vs. 138.5 ± 2.8 in WT mice, n = 8 for each group, p < 0.05) in parallel with attenuated response of intrarenal renin and renal medullary α-ENaC expression. We further examined the direct role of sPRR in renin regulation in As4.1 cells, a renin-expressing cell line isolated from mouse renal tumor and M-1 cells, a mouse cell line derived from the collecting duct. The exposure to sPRR-His in both cell types consistently elevated renin activity, and renin expression at both protein and mRNA levels, all of which were sensitive to inhibition by ICG-001, a β-catenin signaling inhibitor. Together, these results represent strong evidence favoring sPRR as a mediator of AngII-induced hypertension and a master regulator of renin expression at systemic and local levels. Therefore, PRR should be considered as an integrative member of the RAS.

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