Proximal tubular secretion of angiotensin II in rats

1993 ◽  
Vol 264 (5) ◽  
pp. F891-F898 ◽  
Author(s):  
B. Braam ◽  
K. D. Mitchell ◽  
J. Fox ◽  
L. G. Navar
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Enzyme Inhibitor ◽  
Isotonic Saline ◽  
Tubular Secretion ◽  
Ang Ii ◽  
Local Formation ◽  
Enhanced Sensitivity ◽  
Proximal Tubular ◽  
Nanomolar Range

It is now established that all of the components necessary for the local formation of angiotensin II (ANG II) coexist in the kidney and can alter local ANG II production rate. However, data on ANG II concentrations in different compartments within the kidney are limited. Recently, proximal tubule fluid ANG II concentrations in the nanomolar range were reported. Using an ANG II radioimmunoassay procedure with enhanced sensitivity, we performed experiments to explore proximal tubular fluid ANG II levels further and to determine the source of the ANG II. Total free-flow proximal tubular fluid samples (n = 11) had an average ANG II concentration of 13 +/- 2 nM. These concentrations were similar (10 +/- 2 nM) in samples collected into pipettes containing the inhibitors enalaprilat and EDTA (n = 17). Fluid collected from blocked proximal tubules that were perfused with artificial tubular fluid showed similar ANG II concentrations both in the presence (22 +/- 3 nM) and absence (22 +/- 4 nM) of the angiotensin-converting-enzyme inhibitor, enalaprilat, in the perfusate. Plasma ANG II concentrations were much lower and averaged 155 +/- 26 pM. Isotonic saline expansion lowered plasma ANG II levels to 30 +/- 5 pM (P < 0.01) but did not significantly decrease intraluminal ANG II (8 +/- 1 nM). These data provide further evidence that intratubular ANG II concentrations are in the nanomolar range and are regulated independently of the plasma ANG II levels. The data obtained from perfused tubules indicate that the proximal tubule adds substantial amounts of ANG II or a precursor into the tubular lumen.

scholarly journals Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli

2010 ◽  
Vol 298 (1) ◽  
pp. F177-F186 ◽  
Author(s):  
Anne D. M. Riquier-Brison ◽  
Patrick K. K. Leong ◽  
Kaarina Pihakaski-Maunsbach ◽  
Alicia A. McDonough
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Flow Rate ◽  
Enzyme Inhibitor ◽  
Volume Flow Rate ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Water Reabsorption ◽  
Associated Proteins ◽  
Gradient Fractionation

Angiotensin II (ANG II) stimulates proximal tubule (PT) sodium and water reabsorption. We showed that treating rats acutely with the angiotensin-converting enzyme inhibitor captopril decreases PT salt and water reabsorption and provokes rapid redistribution of the Na+/H+ exchanger isoform 3 (NHE3), Na+/Pi cotransporter 2 (NaPi2), and associated proteins out of the microvilli. The aim of the present study was to determine whether acute ANG II infusion increases the abundance of PT NHE3, NaPi2, and associated proteins in the microvilli available for reabsorbing NaCl. Male Sprague-Dawley rats were infused with a dose of captopril (12 μg/min for 20 min) that increased PT flow rate ∼20% with no change in blood pressure (BP) or glomerular filtration rate (GFR). When ANG II (20 ng·kg−1·min−1 for 20 min) was added to the captopril infusate, PT volume flow rate returned to baseline without changing BP or GFR. After captopril, NHE3 was localized to the base of the microvilli and NaPi2 to subapical cytoplasmic vesicles; after 20 min ANG II, both NHE3 and NaPi2 redistributed into the microvilli, assayed by confocal microscopy and density gradient fractionation. Additional PT proteins that redistributed into low-density microvilli-enriched membranes in response to ANG II included myosin VI, DPPIV, NHERF-1, ezrin, megalin, vacuolar H+-ATPase, aminopeptidase N, and clathrin. In summary, in response to 20 min ANG II in the absence of a change in BP or GFR, multiple proteins traffic into the PT brush-border microvilli where they likely contribute to the rapid increase in PT salt and water reabsorption.

Superficial nephron responses to peritubular capillary infusions of angiotensins I and II

1987 ◽  
Vol 252 (5) ◽  
pp. F818-F824 ◽  
Author(s):  
K. D. Mitchell ◽  
L. G. Navar
Keyword(s):  
Enzyme Inhibitor ◽  
Isotonic Saline ◽  
Tubular Reabsorption ◽  
Ang Ii ◽  
Peritubular Capillary ◽  
Single Nephron ◽  
Proximal Tubular ◽  
Flow Pressure ◽  
Proximal Tubular Reabsorption ◽  
Stop Flow

Proximal tubular reabsorption, stop-flow pressure (SFP), and single nephron glomerular filtration rate (SNGFR) were measured in the absence of and during infusion of an isotonic saline solution containing either angiotensin I (ANG I; 10(-6) to 10(-5) M) or angiotensin II (ANG II; 10(-9) to 10(-7) M) into an adjacent peritubular capillary at a rate of 20 nl/min. Dilution of the infused ANG I and ANG II occurred in the peritubular capillary blood and as the peptides diffused into the interstitium. Infusion of either 10(-7) M ANG II or 10(-5) M ANG I increased proximal fractional fluid reabsorption (FRH2O) and decreased both SFP and SNGFR. There were no significant changes in FRH2O or SNGFR during infusion of 10(-5) M ANG I when the converting enzyme inhibitor enalaprilat (MK 422, 10(-3) M) was added to the infusate. Similarly, peritubular infusion at lower concentrations of either ANG II (10(-9) or 10(-8) M) or ANG I (10(-6) M) did not alter FRH2O, SFP, or SNGFR. These data indicate that conversion of ANG I to ANG II can occur in the peritubular capillary or interstitial environment and that increases above the normal endogenous levels in the postglomerular interstitial ANG II concentration can enhance proximal tubular reabsorption and increase preglomerular resistance and thereby reduce SNGFR.

Abstract 405: Novel Signaling Mechanisms by Which Intracellular Angiotensin II Induces Na + /HCO 3 - CotransporterExpression In The Proximal Tubule of The Kidney

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Julia L Cook ◽  
Ulrich Hopfer ◽  
Jia L Zhuo
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Signaling Pathways ◽  
Map Kinases ◽  
Ang Ii ◽  
Wild Type ◽  
Bicarbonate Reabsorption ◽  
Signaling Mechanisms ◽  
Proximal Tubular ◽  
Deficient Mice

Previous studies have shown that endocrine and/or paracrine angiotensin II (ANG II) plays an important role in the regulation of sodium and bicarbonate reabsorption in the proximal tubule of the kidney. However, it is not known whether intracellular (or intracrine) ANG II also plays a role in these responses in the proximal tubule. The present study tested the hypothesis that overexpression of an intracellular cyan fluorescent fusion protein of ANG II (ECFP/ANG II) in the proximal tubule of the kidney induces the expression of the Na + /HCO 3 - cotransporter via MAPK- and NF-kB signaling pathways. To test the hypothesis, transport-competent mPCTs from wild-type and type 1a ANG II receptor-deficient mice (AT 1a -KO) were transfected with ECFP/ANG II, and treated with the AT 1 receptor blocker losartan, the MEK1/MEK2 inhibitor U0126, or the NF-κB inhibitor RO 106-9920. In wild-type mPCT cells, the expression of ECFP/ANG II more than doubled total and/or phosphorylated NHE3 antiporter and Na + /HCO 3 - cotransporter proteins (p<0.01). These response were accompanied by more than threefold increases in phospho-ERK 1/2, p65 subunit of NF-κB, and phospho-IKKα/β (Ser 176/180) proteins (p<0.01). Pretreatment of mPCT cells with losartan, U0126, or RO 106-9920 significantly blocked the effects of ECFP/ANG II (p<0.01). Furthermore, the effects of ECFP/ANG II were significantly attenuated in mPCT cells of AT 1a -KO mice (p<0.01),. In wild-type C57BL/6J mice, adenovirus-mediated overexpression of ECFP/ANG II selectively in the proximal tubule of the kidney, driven by the sodium and glucose cotransporter 2 (sglt2) promoter, significantly increased blood pressure, total and/or phosphorylated NHE3 and Na + /HCO 3 - proteins, and proximal tubular lithium reabsorption (p<0.01). These responses to ECFP/ANG II as observed in C57BL/6J mice were also attenuated in AT 1a -KO mice (p<0.01). Our results strongly suggest that intracellular ANG II may induce NHE3 and Na + /HCO 3 - expression, and increase proximal tubular sodium and bicarbonate reabsorption via AT 1a receptor-mediated activation of MAP kinases ERK 1/2 and NF-κB signaling pathways.

Renal hemodynamic responses to increased renal venous pressure: role of angiotensin II

1982 ◽  
Vol 243 (3) ◽  
pp. F260-F264 ◽  
Author(s):  
P. R. Kastner ◽  
J. E. Hall ◽  
A. C. Guyton
Keyword(s):  
Angiotensin Ii ◽  
Filtration Rate ◽  
Enzyme Inhibitor ◽  
Venous Pressure ◽  
Renin Secretion ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Filtration Fraction ◽  
A Value

Studies were performed to quantitate the effects of progressive increases in renal venous pressure (RVP) on renin secretion (RS) and renal hemodynamics. RVP was raised in 10 mmHg increments to 50 mmHg. Renin secretion rate increased modestly as RVP was increased to 30 mmHg and then increased sharply after RVP exceeded 30 mmHg. Glomerular filtration rate (GFR), renal blood flow (RBF), and filtration fraction (FF) did not change significantly when RVP was elevated to 50 mmHg. GFR and RBF were also measured after the renin-angiotension system (RAS) was blocked with the angiotensin converting enzyme inhibitor (CEI) SQ 14225. After a 60-min CEI infusion, RBF was elevated (32%), GFR was unchanged, FF was decreased, and total renal resistance (TRR) was decreased. As RVP was increased to 50 mmHg, GFR and FF decreased to 36.3 and 40.0% of control, respectively, RBF returned to a value not significantly different from control, and TRR decreased to 44.8% of control. The data indicate that the RAS plays an important role in preventing reductions in GFR during increased RVP because blockade of angiotensin II (ANG II) formation by the CEI results in marked decreases in GFR at high RVPs. The decreases in GFR after ANG II blockade and RVP elevation were not due to lack of renal vasodilation, since TRR was maintained below while RBF was maintained either above or at the pre-CEI levels.

Interactions between adenosine and angiotensin II in controlling glomerular filtration

1985 ◽  
Vol 248 (3) ◽  
pp. F340-F346 ◽  
Author(s):  
J. E. Hall ◽  
J. P. Granger ◽  
R. L. Hester
Keyword(s):  
Renal Failure ◽  
Angiotensin Ii ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Renal Vasoconstriction ◽  
Ischemic Renal Failure ◽  
Constrictor Response

This study examined interactions between adenosine (Ado) and angiotensin II (ANG II) in controlling renal blood flow (RBF) and glomerular filtration rate (GFR). In six normal dogs, intrarenal Ado infusion (1.0 mumol/min) transiently decreased RBF, but during sustained Ado infusion RBF increased to 122 +/- 7% of control, although GFR remained at 75 +/- 6% of control. Blockade of ANG II formation with the converting enzyme inhibitor SQ 14225 (n = 6) almost abolished the transient decrease in RBF but did not prevent the sustained fall in GFR caused by Ado. When circulating ANG II was held constant by intravenous infusion of SQ 14225 and 20 ng . kg-1 . min-1 of ANG II (n = 6), Ado transiently decreased RBF but the return of RBF was much slower than in normal dogs and RBF did not increase above control. Maintenance of constant circulating ANG II did not prevent Ado-mediated decreases in GFR. These observations suggest that Ado-mediated reductions in GFR do not depend entirely on ANG II and may be due to dilation of efferent arterioles by Ado. However, the transient renal vasoconstriction caused by Ado depends on ANG II, and data from this study suggest that part of the waning constrictor response to Ado is due to suppression of renin secretion and endogenous ANG II formation. In circumstances where high ANG II levels are maintained (i.e., ischemic renal failure), Ado may be capable of causing sustained renal vasoconstriction.

Thermal responses to central angiotensin II, SQ 20881, and dopamine infusions in sheep

1985 ◽  
Vol 248 (3) ◽  
pp. R371-R377 ◽  
Author(s):  
B. S. Huang ◽  
M. J. Kluger ◽  
R. L. Malvin
Keyword(s):  
Angiotensin Ii ◽  
Body Temperature ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Significant Rise ◽  
Ang Ii ◽  
Deep Body Temperature ◽  
Angiotensin System ◽  
Conscious Sheep

The thermoregulatory role of brain angiotensin II (ANG II) was tested by intracerebroventricular (IVT) infusion of ANG II or the converting enzyme inhibitor SQ 20881 (SQ) in 15 conscious sheep. Deep body temperature decreased 0.30 +/- 0.07 degree C (SE) during the 3-h period of IVT ANG II (25 ng/min) infusion (P less than 0.05) and increased 0.50 +/- 0.13 degree C during IVT SQ (1 microgram/min) infusion (P less than 0.01). To determine whether the rise in body temperature after IVT SQ infusion might be the result of a central renin-angiotensin system (RAS), SQ was infused IVT in five conscious sheep 20 h after bilateral nephrectomy. This resulted in a significant rise in body temperature of 0.28 +/- 0.05 degree C (P less than 0.05). When vasopressin antidiuretic hormone (ADH) was infused intravenously at the same time of IVT SQ infusion, the rise in temperature was depressed, but ADH did not lower the temperature below basal. IVT dopamine (20 micrograms/min) increased body temperature by 0.40 +/- 0.04 degree C (P less than 0.01), which was qualitatively similar to the result with IVT SQ. These data support the hypothesis that endogenous brain ANG II may play a role in thermoregulation. Furthermore, plasma ADH level, regulated in part by brain ANG II, is probably not the mediator of that thermoregulation. The similar effects of IVT dopamine and SQ on body temperature strengthen the hypothesis that dopamine may be involved in the central action of brain ANG II.

Discovery of L-162,313: a nonpeptide that mimics the biological actions of angiotensin II

1995 ◽  
Vol 268 (3) ◽  
pp. R820-R823 ◽  
Author(s):  
S. D. Kivlighn ◽  
W. R. Huckle ◽  
G. J. Zingaro ◽  
R. A. Rivero ◽  
V. J. Lotti ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Agonist ◽  
Enzyme Inhibitor ◽  
Pressor Response ◽  
Ang Ii ◽  
Aortic Smooth Muscle Cell ◽  
Maximum Increase ◽  
Aortic Smooth Muscle ◽  
Biological Actions

L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n- butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]- imadazo[4,5-b]pyridine) is a nonpeptide that mimics the biological actions of angiotensin II (ANG II). The intravenous administration of L-162,313 increased blood pressure in the rat. The maximum increase in mean arterial pressure (MAP) was not different from the maximum response to ANG II in the same preparation. However, the duration of the pressor response after L-162,313 greatly exceeded that of ANG II. Pretreatment with ANG II receptor antagonists, L-158,809 (AT1 selective) or saralasin, blocked the L-162,313-induced increase in MAP. Enalaprilat, an angiotensin-converting enzyme inhibitor, failed to block the MAP response to L-162,313. In vitro, L-162,313-activated phosphoinositide turnover in rat aortic smooth muscle cell cultures was also blocked by L-158,809 and losartan (DuP-753). Therefore, L-162,313 is the first reported nonpeptide ANG II receptor agonist.

scholarly journals Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Xiao Chun Li ◽  
Ana Paula Oliveira Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Xu Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Normal Blood ◽  
Ang Ii ◽  
Normal Blood Pressure ◽  
Wild Type ◽  
Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

scholarly journals Retinal angiotensin II and angiotensin-(1-7) response to hyperglycemia and an intervention with captopril

2018 ◽  
Vol 19 (3) ◽  
pp. 147032031878932 ◽  
Author(s):  
Preenie deS Senanayake ◽  
Vera L Bonilha ◽  
John W Peterson ◽  
Yoshiro Yamada ◽  
Sadashiva S Karnik ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Enzyme Inhibitor ◽  
Müller Cells ◽  
Plexiform Layer ◽  
Confocal Imaging ◽  
Inner Plexiform Layer ◽  
Ang Ii ◽  
Muller Cells ◽  
Photoreceptor Layer ◽  
Angiotensin Peptides

Hypothesis: Hyperglycemia decreases angiotensin-(1-7), the endogenous counter-regulator of angiotensin II in the retina. Materials and methods: The distribution and levels of retinal angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) were evaluated by confocal imaging and quantitative immunohistochemistry during the development of streptozotocin-induced diabetes in rats. Results: In the nondiabetic eye, Ang II was localized to the endfeet of Müller cells, extending into the cellular processes of the inner plexiform layer and inner nuclear layer; Ang-(1-7) showed a wider distribution, extending from the foot plates of the Müller cells to the photoreceptor layer. Eyes from diabetic animals showed a higher intensity and extent of Ang II staining compared with nondiabetic eyes, but lower intensity with a reduced distribution of Ang-(1-7) immunoreactivity. Treatment of the diabetic animals with the angiotensin-converting enzyme inhibitor (ACEI) captopril showed a reduced intensity of Ang II staining, whereas increased intensity and distribution were evident with Ang-(1-7) staining. Conclusions: These studies reveal that pharmacological inhibition with ACEIs may provide a specific intervention for the management of the diabetes-induced decline in retinal function, reversing the profile of the endogenous angiotensin peptides closer to the normal condition.

Abstract 41: Fructose Stimulates Na/H Exchanger 3 Activity and Enhances the Ability of Angiotensin II to Activate Na/H Exchanger 3 in the Proximal Tubule

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pablo Cabral ◽  
Nancy Hong ◽  
Jeffrey Garvin
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Physiological Saline ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Basal Rate ◽  
Low Concentrations ◽  
Sprague Dawley Rats ◽  
High Fructose ◽  
Salt Sensitive Hypertension

Consumption of high-fructose corn syrup as a sweetener has increased dramatically. Fructose has been implicated in the epidemic of diabetes, obesity and hypertension including salt-sensitive hypertension. However, the mechanisms are poorly understood. The proximal nephron reabsorbs 60-70% of the fluid and Na, and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport has been implicated in several forms of hypertension. We hypothesized that fructose stimulates NHE3 activity and enhances the ability of angiotensin II (ANG II) to activate NHE3 in the proximal tubule. To test our hypothesis we isolated and perfused proximal tubules from Sprague Dawley rats. NHE3 activity was measured as the recovery of intracellular pH after an NH4Cl acid pulse using the pH sensitive dye BCECF. The rate of pH recovery was measured in Fluorescent Units per second (FU/sec). In the presence of a 5.5 mM glucose-containing physiological saline the basal rate of pH recovery was 3.1 ± 0.8 FU/sec. When the luminal solution was exchanged to a 0.6 mM glucose + 5 mM fructose-containing physiological saline in a second period, the rate of pH recovery increased to 5 ± 1 FU/sec (p<0.03, n=8).To study whether this effect was due to the addition of fructose or the removal of glucose to the lumen, we performed a separate set of experiments where 5 mM glucose was substituted for 5 mM fructose. In the presence of 0.6 mM glucose the basal rate of pH recovery was 3.6 ± 1.5 FU/sec. When 5 mM fructose was added the rate of pH recovery increased to 5.9 ± 2 FU/sec (p<0.02, n=5). Control experiments showed no differences between periods when 5 mm glucose was added back to the luminal perfusate. Finally, we tested the effect of low concentrations of ANG II in the presence or absence of luminal fructose. In the presence of 5.5 mM glucose, ANG II 10-12 M did not affect the rate of pH recovery (change: -1.1 ± 0.5 FU/sec, n=9). However, in the presence of 5 mM fructose, ANG II increased the rate of pH recovery (change: 4.0 ± 2.2 FU/sec, p< 0.03 n=6). We conclude that acute treatment with fructose stimulates NHE3 activity and enhances the ability of ANG II to activate NHE3 in the proximal tubule. These results may partially explain the mechanism by which a fructose diet induces hypertension.

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