Changes in NOS activity and protein expression  during acute and prolonged ANG II administration

The aim of this study was to assess the effects of acute or prolonged increases of ANG II on nitric oxide synthase (NOS) activities and protein expression in mesenteric resistance vessels, left ventricle, renal cortex, and renal medulla. The response of NOS activities to ANG II is compared with that induced by phenylephrine. ANG II or phenylephrine were infused over either 3 h or 3 days to conscious rats. NOS activity was examined by measuring the rate of conversion ofl-[14C]arginine tol-[14C]citrulline. Protein levels of endothelial (e) and neuronal (n) NOS were determined by Western blot analysis. Arterial pressure (AP) increased ( P < 0.05) during acute and prolonged ANG II infusion. Ca2+-dependent NOS activity values (pmol of citrulline · min−1 · g wet wt−1) for control rats were 21 ± 9 in mesenteric arteries, 13 ± 7 in left ventricle, 14 ± 8 in renal cortex, and 411 ± 70 in renal medulla. Acute ANG II infusion increased ( P < 0.05) Ca2+-dependent NOS activity in renal cortex and renal medulla (81 ± 18 and 611 ± 48, respectively), but no differences were found in mesenteric arteries and left ventricle with respect to control rats. In contrast to the renal changes in NOS activity, acute ANG II infusion did not modify eNOS or nNOS expression in any of the tissues examined. Prolonged ANG II infusion increased ( P < 0.05) Ca2+-dependent NOS activity in mesenteric arteries (70 ± 17), renal cortex (104 ± 31), and left ventricle (49 ± 8) and did not elicit changes in renal medulla. After a prolonged ANG II infusion, eNOS and nNOS levels increased in all tissues examined with the exception of eNOS in the mesenteric arteries and nNOS in the left ventricle, which were not altered. Acute and prolonged phenylephrine infusion elevated AP to a similar extent as ANG II but only elicited significant increments of Ca2+-dependent NOS activity in renal cortex. These data indicate that acute and prolonged elevations in ANG II upregulate Ca2+-dependent NOS activity and protein expression in different tissues related to the control of blood pressure. However, these ANG II effects are heterogeneous with respect to the tissue implicated, the time course of the stimulation, and the NOS isoform involved. Phenylephrine only induces a significant elevation of Ca2+-dependent NOS activity in renal cortex.

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Abstract 559: Augmented Renal Levels of PDGFß And PDGFß Receptors in Cyp1a1-Ren2 Transgenic Rats With Angiotensin II-Dependent Malignant Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a559 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Kenneth D Mitchell ◽

Minolfa C Prieto ◽

Dale M Seth ◽

Porcha D Davis ◽

Camille Bourgeois ◽

...

Keyword(s):

Imatinib Mesylate ◽

Renal Injury ◽

Renal Cortex ◽

Renal Medulla ◽

Receptor Activation ◽

Malignant Hypertension ◽

Pdgf Receptor ◽

Ang Ii ◽

Transgenic Rats ◽

Protein Levels

PDGF receptor antagonism with imatinib mesylate prevents the renal injury, proteinuria and augmented urinary ANG II excretion independent of changes in blood pressure that occur in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. These findings suggest that arterial pressure-dependent increases in PDGFβ protein levels and PDGFβ receptor activation contribute importantly to the marked renal functional and morphological derangements that occur in ANG II-dependent malignant hypertension. To address this issue, the present study was performed to determine the protein levels of PDGFβ and PDGFβ receptors in renal cortical and medullary tissue from kidneys of hypertensive Cyp1a1-Ren2 transgenic rats. Male Cyp1a1-Ren2 rats were fed a diet containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension (n=5) or a non-I3C containing diet (controls, n=6). Rats induced with I3C developed malignant hypertension and exhibited increases in PDGFβ protein levels in both the renal cortex (0.046±0.002 vs.0.026±0.003 AU, P<0.05) and renal medulla (0.054±0.007 vs.0.026±0.003 AU, P<0.05), and elevated PDGFβ receptor levels in both renal cortex (0.26±0.03 vs.0.12±0.02 AU, P<0.05) and renal medulla (0.60±0.06 vs.0.21±0.02 AU, P<0.05). In a separate group (n=5), rats were chronically treated with the PDGF receptor antagonist, imatinib mesylate, by oral gavage (60 mg/kg/d) starting 3 days before initiating I3C induction and maintained on imatinib for the 10 day duration of I3C administration. Chronic PDGF receptor blockade prevented the increase in PDGFβ protein levels in both renal cortical and medullary tissues (0.027±0.004 vs. 0.026±0.003 and 0.029±0.005 vs. 0.026±0.003 AU, respectively) but did not influence the elevated PDGFβ receptor levels in either renal cortex (0.23±0.02 vs. 0.26±0.02 AU) or renal medulla (0.46±0.03 vs.0.60±0.06 AU). These data demonstrate that both PDGFβ protein and PDGFβ receptor levels are elevated in both renal cortex and medulla in ANG II-dependent malignant hypertension. Such elevated levels may contribute to the renal injury and the increased urinary ANG II excretion in ANG II-dependent malignant hypertension.

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Abstract P219: Losartan Prevents The Recruitment Of Renal M1-like Macrophages And Dendritic Cells In Medulla Of Angiotensin Ii Hypertensive Mice

Hypertension ◽

10.1161/hyp.78.suppl_1.p219 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Patricio A Araos ◽

Andrés Guzmán ◽

Stefanny M Figueroa ◽

Javier Reyes ◽

Cristián A Amador

Keyword(s):

Dendritic Cells ◽

Immune Cells ◽

Renal Cortex ◽

Renal Medulla ◽

Ang Ii ◽

Mhc Ii ◽

Treatment Changes ◽

Antigen Presenting

Immune cells play a major role in the development and progression of hypertension. Previous studies have shown that antigen presenting cells (APCs), such as macrophages (Mø) and dendritic cells (DCs) are particularly abundant in kidney. However, the relevance of these renal APCs on hypertension and whether their distribution change during the anti-hypertensive treatment remain unknow. We evaluated whether losartan (Los) treatment changes the abundance of APCs in the renal cortex and medulla in Angiotensin (Ang) II-infused mice.Male C57BL/6 mice (8-12wo) were treated with AngII (490ng/Kg/min), AngII+Los (20mg/Kg/day) or Vehicle for 14 days (n=4-6). Systolic blood pressure (SBP) was measured by the tail cuff method, and renal cortex/medulla were isolated for the measurements of: APCs (MHC-II + :CD11c + ), DCs (APCs:F4/80 - :CD64 - /CD103 + for type-1 DCs, or APCs:F4/80 - :CD64 - :CD11b + for type-2 DCs), and M1-like Mø (APCs:F4/80 - :CD64 + :CD11b + ), by flow cytometry.Los treatment prevented the increased SBP (AngII+Los=118.8±6.4 mmHg vs. AngII=158.0±21.1 mmHg; p<0.001), and the APCs recruitment in renal cortex (AngII+Los=23.2±2.7 vs. AngII=36.0±5.9%; p<0.01) and in renal medulla (Veh=16.3±7.7; AngII=26.3±4,7; AngII+Los=14.9±3.3%; p<0.05) induced by AngII. In addition, we observed an increase of DC2 and M1-like Mø recruitments in renal medulla of AngII mice (DC2 Veh =29.0±5.0 vs. DC2 AngII =45.5±7.3%; p<0.05; M1 Veh =44.8±7.5 vs. M1 AngII =58.3±5.3%; p<0.05), which were prevented by Los treatment (DC2 AngII+Los =27.1±6.8%; p<0.05; M1 AngII+Los =47.0±3.5%; p<0.05). Interestingly, we did not observe differences between groups on M1-like Mø, and DC2 populations in renal cortex. However, Los treatment prevented the increase of DC1 on renal cortex (Veh=2.1±1.4; AngII=5.2±2.4; AngII+Los=2.1±0.8%; p<0.05), without differences between groups at medullar level.Our results show that Los treatment has a differential effect on the APCs populations in renal cortex and medulla, suggesting that renal APCs have different participations on hypertension according their microenvironment.Supported by Fondecyt #1201251 and #3201016

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COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla

AJP Renal Physiology ◽

10.1152/ajprenal.00548.2013 ◽

2014 ◽

Vol 307 (1) ◽

pp. F25-F32 ◽

Cited By ~ 31

Author(s):

Fei Wang ◽

Xiaohan Lu ◽

Kexin Peng ◽

Li Zhou ◽

Chunling Li ◽

...

Keyword(s):

Angiotensin Ii ◽

Protein Expression ◽

Renal Medulla ◽

Receptor Expression ◽

Ang Ii ◽

Cox 2 ◽

Renin Content

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

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Effects of chronic cold exposure on the endothelin system

Journal of Applied Physiology ◽

10.1152/japplphysiol.01407.2005 ◽

2006 ◽

Vol 100 (5) ◽

pp. 1719-1726 ◽

Cited By ~ 23

Author(s):

Gin-Fu Chen ◽

Zhongjie Sun

Keyword(s):

Epithelial Cells ◽

Cold Exposure ◽

Renal Cortex ◽

Renal Medulla ◽

Immunohistochemical Analysis ◽

Receptor Expression ◽

Mesenteric Arteries ◽

Receptor Protein ◽

Cold Temperatures ◽

Endothelin System

Cold temperatures have adverse effects on the human cardiovascular system. Endothelin (ET)-1 is a potent vasoconstrictor. We hypothesized that cold exposure increases ET-1 production and upregulates ET type A (ETA) receptors. The aim of this study was to determine the effect of cold exposure on regulation of the ET system. Four groups of rats (6–7 rats/group) were used: three groups were exposed to moderate cold (6.7 ± 2°C) for 1, 3, and 5 wk, respectively, and the remaining group was maintained at room temperature (25°C) and served as control. Cold exposure significantly increased ET-1 levels in the heart, mesenteric arteries, renal cortex, and renal medulla. Cold exposure increased ETA receptor protein expression in the heart and renal cortex. ET type B (ETB) receptor expression, however, was decreased significantly in the heart and renal medulla of cold-exposed rats. Cold exposure significantly increased the ratio of ETA to ETB receptors in the heart. An additional four groups of rats (3 rats/group) were used to localize changes in ETA and ETB receptors at 1, 3, and 5 wk of cold exposure. Immunohistochemical analysis showed an increase in ETA, but a decrease in ETB, receptor immunoreactivity in cardiomyocytes of cold-exposed rats. Increased ETA receptor immunoreactivity was also found in vascular smooth muscle cells of cold-exposed rats. Cold exposure increased ETA receptor immunoreactivity in tubule epithelial cells in the renal cortex but decreased ETB receptor immunoreactivity in tubule epithelial cells in the renal medulla. Therefore, cold exposure increased ET-1 production, upregulated ETA receptors, and downregulated ETB receptors.

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Increased activity and expression of Ca2+-dependent NOS in renal cortex of ANG II-infused hypertensive rats

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.5.f797 ◽

1999 ◽

Vol 277 (5) ◽

pp. F797-F804 ◽

Cited By ~ 17

Author(s):

So Yeon Chin ◽

Kailash N. Pandey ◽

Shang-Jin Shi ◽

Hiroyuki Kobori ◽

Carol Moreno ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Renal Cortex ◽

Renal Medulla ◽

Ang Ii ◽

Sprague Dawley ◽

Hypertensive Rats ◽

Differential Distribution ◽

Cortical Blood Flow ◽

Renal Cortical Blood Flow

We have previously demonstrated that nitric oxide (NO) exerts a greater modulatory influence on renal cortical blood flow in ANG II-infused hypertensive rats compared with normotensive rats. In the present study, we determined nitric oxide synthase (NOS) activities and protein levels in the renal cortex and medulla of normotensive and ANG II-infused hypertensive rats. Enzyme activity was determined by measuring the rate of formation ofl-[14C]citrulline froml-[14C]arginine. Western blot analysis was performed to determine the regional expression of endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms in the renal cortex and medulla of control and ANG II-infused rats. Male Sprague-Dawley rats were prepared by the infusion of ANG II at a rate of 65 ng/min via osmotic minipumps implanted subcutaneously for 13 days and compared with sham-operated rats. Systolic arterial pressures were 127 ± 2 and 182 ± 3 mmHg in control ( n = 13) and ANG II-infused rats ( n = 13), respectively. The Ca2+-dependent NOS activity, expressed as picomoles of citrulline formed per minute per gram wet weight, was higher in the renal cortex of ANG II-infused rats (91 ± 11) than in control rats (42 ± 12). Likewise, both eNOS and nNOS were markedly elevated in the renal cortex of the ANG II-treated rats. In both groups of rats, Ca2+-dependent NOS activity was higher in the renal medulla than in the cortex; however, no differences in medullary NOS activity were observed between the groups. Also, no differences in medullary eNOS levels were observed between the groups; however, medullary nNOS was decreased by 45% in the ANG II-infused rats. For the Ca2+-independent NOS activities, the renal cortex exhibited a greater activity in the control rats (174 ± 23) than in ANG II-infused rats (101 ± 10). Similarly, cortical iNOS was greater by 47% in the control rats than in ANG II-treated rats. No differences in the activity were found for the renal medulla between the groups. There was no detectable signal for iNOS in the renal medulla for both groups. These data indicate that there is a differential distribution of NOS activity, with the Ca2+-dependent activity and protein expression higher in the renal cortex of ANG II-infused rats compared with control rats, and support the hypothesis that increased constitutive NOS activity exerts a protective effect in ANG II-induced hypertension to maintain adequate renal cortical blood flow.

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Abstract P342: Vascular Protein Oxidation and Redox Proteomics in Hypertension

Hypertension ◽

10.1161/hyp.68.suppl_1.p342 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Sofia Tsiropoulou ◽

Augusto C Montezano ◽

Alan Scott ◽

Richard J Burchmore ◽

Rhian M Touyz

Keyword(s):

Vascular Injury ◽

Protein Oxidation ◽

Vascular Function ◽

Tyrosine Phosphatase ◽

Redox Status ◽

Mesenteric Arteries ◽

Ang Ii ◽

Protein Levels ◽

Proteomic Data ◽

Anti Oxidant

In hypertension (HTN) mechanisms whereby protein oxidation regulates vascular function remain unclear. We hypothesise that increased ROS promote a shift of oxidative post-translational protein modifications from reversible to irreversible forms, leading to aberrant redox signalling and vascular injury. VSMC from mesenteric arteries of normotensive (WKY) and hypertensive (SHRSP) rats were stimulated with Ang II (10 -7 M) in the presence/absence of PEG-catalase (1000U/ml) or tempol (10 -5 M). Protein carbonylation was assessed by oxyblot and protein sulfenylation by DCP-Rho1 fluorescent probe. Protein tyrosine phosphatase (PTP)-oxidation, peroxiredoxin hyperoxidation (PRXSO3), γH2AX, Bcl2 levels were assessed by immunoblotting. DiGE and CyDye labelling screened for reversibly oxidised thiol proteome. Irreversible carbonylation and PRXSO3 were increased in SHRSP (fold change (FC)=1.29 and 2.77, p<0.05). Ang II-stimulation did not alter carbonylation levels. Reversible sulfenylation and thiol-proteome oxidation were reduced in SHRSP (FC=-1.18, p<0.05 and 13.6% (253 spots)). Ang II-treatment increased sulfenylation in WKY (FC=1.08, p<0.05) and SHRSP (FC=1.23, p<0.001); an effect inhibited by catalase. Reversible PTP oxidation was increased in WKY and SHRSP (FC=1.92 and 2.42, p<0.05), versus irreversible levels. Irreversible PTP oxidation tended to be higher in SHRSP. Ang II increased reversible PTP oxidation only in WKY (FC=1.27, p<0.05) and it was prevented by tempol. Ang II-stimulation increased protein levels of γH2AX (DNA damage) (FC=1.76, p<0.05) and Bcl2 (anti-apoptotic) (FC=2, p<0.05) in WKY. Proteomic data, filtered for FC>2, detected 1777 spots with 21% being differentially oxidised between WKY and SHRSP. Candidate proteins differentially oxidized between WKY and SHRSP include annexin A1 (-2.29) and galectin-1 (2.83). These results demonstrate altered redox status in HTN characterised by increased protein hyperoxidation and decreased reversible oxidation, in combination with decreased anti-oxidant capacity. Moreover, our findings identify novel candidate oxidized proteins implicated in VSMC motility, proliferation and signalling which may contribute to oxidative vascular injury in HTN.

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Renal expression and urinary excretion of aquaporin-2 in postobstructive uropathy in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0481 ◽

2021 ◽

pp. 1-8

Author(s):

Anabel Brandoni ◽

Adriana M. Torres

Keyword(s):

Time Course ◽

Renal Cortex ◽

Renal Medulla ◽

Obstructive Nephropathy ◽

Kidney Cortex ◽

Mrna Levels ◽

Whole Cell Lysate ◽

Aquaporin 2 ◽

Immunohistochemical Techniques ◽

Apical Membranes

This work assessed the time course of water renal management together with aquaporin-2 (AQP2) kidney expression and urinary AQP2 levels (AQP2u) in obstructive nephropathy. Adult male Wistar rats were monitored after 1, 2, and 7 days of bilateral ureteral release (bilateral ureteral obstruction (BUO); BUO-1, BUO-2 and BUO-7). Renal water handling was evaluated using conventional clearance techniques. AQP2 levels were assessed by immunoblotting and immunohistochemical techniques. AQP2 expression in apical membranes was downregulated in BUO-1 rats and upregulated both in BUO-2 and BUO-7 animals. AQP2 protein expression in whole cell lysate fraction from kidney cortex and medulla were significantly decreased in all the experimental groups. Concomitantly, mRNA levels of AQP2 decreased in renal medulla of all groups and in renal cortex from BUO-1; however, in renal cortex from BUO-2 and BUO-7 a recovery and an increase in the level of AQP2 mRNA were, respectively, observed. BUO-7 group showed a significant increase in AQP2u. The alterations observed in apical membranes AQP2 expression could explain, at least in part, the evolution time of water kidney management in the postobstructive phase of BUO. Additionally, the AQP2u increase after 7 days of ureteral release may be postulated as a biomarker of improvement in the kidney function.

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Proliferating CLL Cells Express Abundant But Transcriptionally Compromised TP53 Protein

Blood ◽

10.1182/blood.v122.21.4134.4134 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4134-4134 ◽

Cited By ~ 1

Author(s):

Jesvin J Samuel ◽

Alice H Wignall ◽

Hishyar Najeeb ◽

Aneela Majid ◽

Sandrine Jayne ◽

...

Keyword(s):

Dna Damage ◽

Protein Expression ◽

Time Course ◽

Target Genes ◽

Wild Type ◽

Proliferating Cells ◽

Protein Levels ◽

L Cells ◽

High Level ◽

Tp53 Protein

Abstract Current models of CLL pathogenesis invoke specialized microenvironments within the lymph nodes and bone marrow that harbor proliferating cells. Such proliferating CLL cells are more resistant to current immuno-chemotherapeutic regimens than cells in the peripheral blood and are thought to be the cause of resistant disease. Various models have been used to recapitulate these CLL proliferation centers in vitro, including stimulating cells with CD154 and IL4. We studied 40 patients (6 with p53 mutations/deletions) using this system and observed that >50% of CLL cells undergo proliferation after 72 hours of stimulation, as assessed by Ki67 staining. Unexpectedly, under these conditions we also observed a 30-40 fold induction of TP53 protein in all cases of CLL analyzed, irrespective of TP53 mutational status. Nearly all cells showed increased TP53 protein expression (Figure 1), suggesting that such high-level TP53 protein expression did not hinder cell proliferation. Given that induction of wild-type TP53 protein usually induces cell cycle arrest if not apoptosis, we examined for transcriptional up-regulation of TP53 target genes using a combination of qRT-PCR, RNA arrays and RNA-Seq approaches. 4 out of 12 cases showed induction of some TP53 target genes, but overall there was no consistent pattern of transcriptional up-regulation of target genes, suggesting that the induced TP53 is transcriptionally compromised in CLL cells following CD154/IL4 stimulation. In contrast, DNA damage induced by doxorubicin in CD154/IL4 stimulated cells induced wild type TP53 protein to even higher levels, resulting in TP53 target gene up-regulation and apoptosis, as expected. CD154/IL4 stimulation also induced a 10-fold elevation in ROS levels in all cases. This resulted in significant oxidative DNA damage, as measured by a modified comet assay, which could explain the induction of TP53 in proliferating cells. qRT-PCR and RNA-Seq experiments failed to show a significant increase in TP53 mRNA levels, indicating that elevation of TP53 protein levels was occurring post-transcriptionally. Increased phosphorylation of TP53 at S15 was seen in all cases, which may account for the observed increased protein stability through dissociation from MDM2. All TP53 mRNA isoforms expressed retained transcriptional activation and DNA binding domains. In view of these results, we propose a model whereby oxidative stress induced by proliferation in CLL triggers TP53 protein expression. TP53 becomes phosphorylated but, for reasons that remain unclear, is unable to transactivate its target genes normally and induce cell-cycle arrest. Apoptosis could be suppressed by high-level expression of anti-apoptotic BCL2 proteins. However, TP53 remains able to trigger a full apoptotic response after further DNA damage and a higher threshold of protein levels is reached. Reactivation of the full transcriptional activities of wild-type TP53 in proliferating CLL cells may provide a new therapeutic approach.Figure 1CD154/IL4 stimulation increases CLL proliferation and induces TP53 expression. Top panel: Time course of Ki67 and TP53 expression in CD19+ CLL cells stimulated with rhCD154 and rhIL4. Bottom panel: Representative immunoblot of TP53 expression in CLL cells after 1, 3 and 7 days of co-culture with mouse L cells (NTL) or rhCD154 transfected-L Cells and rhIL4.Figure 1. CD154/IL4 stimulation increases CLL proliferation and induces TP53 expression. Top panel: Time course of Ki67 and TP53 expression in CD19+ CLL cells stimulated with rhCD154 and rhIL4. Bottom panel: Representative immunoblot of TP53 expression in CLL cells after 1, 3 and 7 days of co-culture with mouse L cells (NTL) or rhCD154 transfected-L Cells and rhIL4. Disclosures: No relevant conflicts of interest to declare.

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Increased renin excretion is associated with augmented urinary angiotensin II levels in chronic angiotensin II-infused hypertensive rats

AJP Renal Physiology ◽

10.1152/ajprenal.00339.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. F1195-F1201 ◽

Cited By ~ 42

Author(s):

Liu Liu ◽

Alexis A. Gonzalez ◽

Michael McCormack ◽

Dale M. Seth ◽

Hiroyuki Kobori ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Medulla ◽

Plasma Renin ◽

Tubular Secretion ◽

Sodium Reabsorption ◽

Ang Ii ◽

Sprague Dawley ◽

Hypertensive Rats ◽

Protein Levels ◽

Urinary Levels

Renin expression in principal cells of collecting ducts (CD) is upregulated in angiotensin II (ANG II)-dependent hypertensive rats; however, it remains unclear whether increased CD-derived renin undergoes tubular secretion. Accordingly, urinary levels of renin (uRen), angiotensinogen (uAGT), and ANG II (uANG II) were measured in chronic ANG II-infused Sprague-Dawley rats (80 ng/min for 14 days, n = 10) and sham-operated rats ( n = 10). Systolic blood pressure increased in the ANG II rats by day 5 and continued to increase throughout the study ( day 13; ANG II: 175 ± 10 vs. sham: 116 ± 2 mmHg; P < 0.05). ANG II infusion increased renal cortical and medullary ANG II levels (cortical ANG II: 606 ± 72 vs. 247 ± 43 fmol/g; P < 0.05; medullary ANG II: 2,066 ± 116 vs. 646 ± 36 fmol/g; P < 0.05). Although plasma renin activity (PRA) was suppressed in the ANG II-infused rats (0.3 ± 0.2 vs. 5.5 ± 1.8 ng ANG I·ml−1·h−1; P < 0.05), renin content in renal medulla was increased (12,605 ± 1,343 vs. 7,956 ± 765 ng ANG I·h−1·mg−1; P < 0.05). Excretion of uAGT and uANG II increased in the ANG II rats [uAGT: 1,107 ± 106 vs. 60 ± 26 ng/day; P < 0.0001; uANG II: 3,813 ± 431 vs. 2,080 ± 361 fmol/day; P < 0.05]. By day 13, despite suppression of PRA, urinary prorenin content increased in ANG II rats [15.7 ± 3 vs. 2.6 ± 1 × 10−3 enzyme units excreted (EUE)/day, P < 0.01] as was the excretion rate of renin (8.6 ± 2 × 10−6 EUE/day) compared with sham (2.8 ± 1 × 10−6 EUE/day; P < 0.05). Urinary renin and prorenin protein levels examined by Western blot were augmented ∼10-fold in the ANG II-infused rats. Concomitant AT1 receptor blockade with candesartan prevented the increase. Thus, in ANG II-dependent hypertensive rats with marked PRA suppression, increased urinary levels of renin and prorenin reflect their augmented secretion by CD cells into the luminal fluid. The greater availability of renin and AGT in the urine reflects the capability for intratubular ANG II formation which stimulates sodium reabsorption in distal nephron segments.

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Role of angiotensin II in arterial pressure and renal hemodynamics in rats with altered renal development: age- and sex-dependent differences

AJP Renal Physiology ◽

10.1152/ajprenal.00424.2012 ◽

2013 ◽

Vol 304 (1) ◽

pp. F33-F40 ◽

Cited By ~ 11

Author(s):

Virginia Reverte ◽

Antonio Tapia ◽

Goretti Baile ◽

Juan Gambini ◽

Ignacio Gíménez ◽

...

Keyword(s):

Oxidative Stress ◽

Adverse Event ◽

Angiotensin Ii ◽

Arterial Pressure ◽

Mesenteric Arteries ◽

Renal Development ◽

Ang Ii ◽

Renal Hemodynamic ◽

Age Dependent ◽

Renal Changes

Numerous studies have demonstrated that angiotensin II (ANG II) is involved in hypertension and renal changes occurring as a consequence of an adverse event during renal development. However, it was unknown whether this involvement is sex and age dependent. This study examines whether the increments in arterial pressure (AP) and in the renal sensitivity to ANG II are sex and age dependent in rats with altered renal development. It also evaluates whether the ANG II effects are accompanied by increments in AT1 receptors and oxidative stress. Experiments were performed in 3- to 4- and 10- to 11-mo-old rats treated with vehicle or an AT1 receptor antagonist (ARAnp) during the nephrogenic period. ARAnp-treated rats were hypertensive, but an age-dependent rise in AP was only found in males. Three days of treatment with candesartan (7 mg·kg−1·day−1) led to a fall of AP that was greater ( P < 0.05) in male than in female 10- to 11-mo-old ARAnp-treated rats. Oxidated proteins were elevated ( P < 0.05), and the decrease in AP elicited by candesartan was reduced ( P < 0.05) when these rats are also treated with tempol (18 mg·kg−1·day−1). Hypertension was not maintained by an elevation of AT1 receptors in kidneys and mesenteric arteries. The acute renal hemodynamic response to ANG II (30 ng·kg−1·min−1) was similarly enhanced ( P < 0.05) in both sexes of ARAnp-treated rats at 3–4 but not at 10–11 mo of age. Our results suggest that an adverse event during the nephrogenic period induces an ANG II-dependent increment in AP that is aggravated only in males during aging and that oxidative stress but not an increase in AT1 receptor contributes to the rise in AP. This study also shows that the renal hemodynamic sensitivity to ANG II is transitorily enhanced in both sexes of rats with altered renal development.

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