scholarly journals Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats

2020 ◽  
Vol 318 (3) ◽  
pp. F683-F688 ◽  
Author(s):  
Malou Friederich-Persson ◽  
Patrik Persson
Keyword(s):  
Nitric Oxide ◽  
Oxygen Consumption ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Diabetic Rats ◽  
Kidney Cortex ◽  
Ang Ii ◽  
Kidney Mitochondria ◽  
Receptor Inhibition

Exaggerated activation of the renin-angiotensin-aldosterone system (RAAS) is a key feature in diseases such as hypertension, diabetes, and chronic kidney disease. Recently, an intracellular RAAS was demonstrated with angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors expressed in nuclei and mitochondria. Diabetes is associated with both mitochondrial dysfunction and increased intracellular ANG II concentration in the kidney cortex. The present study investigated the role of ANG II signaling in kidney cortex mitochondria isolated from control and streptozotocin-induced diabetic rats. Mitochondrial oxygen consumption was evaluated after addition of ANG II alone or after preincubation with candesartan (AT1 receptor antagonist), PD-123319 (AT2 receptor antagonist), or the two in combination. ANG II binds to only mitochondrial AT2 receptors in control rats and both AT1 receptors and AT2 receptors in diabetic rats. ANG II decreased oxygen consumption in mitochondria from both control and diabetic rats. ANG II response was reversed to increased oxygen consumption by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. AT1 receptor inhibition did not affect the response to ANG II, whereas AT2 receptor inhibition abolished the response in mitochondria from control rats and reversed the response to increased oxygen consumption through superoxide-induced mitochondrial uncoupling in mitochondria from diabetic rats. ANG II decrease mitochondrial respiration via AT2 receptor-mediated nitric oxide release in both control and diabetic rats. AT1 receptors do not regulate mitochondria function in control rats, whereas ANG II via AT1 receptors increase mitochondria leak respiration in diabetic animals.

Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep

2000 ◽  
Vol 278 (2) ◽  
pp. H353-H359 ◽  
Author(s):  
Donna S. Lambers ◽  
Suzanne G. Greenberg ◽  
Kenneth E. Clark
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Uterine Artery ◽  
Receptor Subtype ◽  
Ang Ii ◽  
Uterine Blood Flow ◽  
Response Curves ◽  
Vascular Responses

The objective was to determine the receptor subtype of angiotensin II (ANG II) that is responsible for vasoconstriction in the nonpregnant ovine uterine and systemic vasculatures. Seven nonpregnant estrogenized ewes with indwelling uterine artery catheters and flow probes received bolus injections (0.1, 0.3 and 1 μg) of ANG II locally into the uterine artery followed by a systemic infusion of ANG II at 100 ng ⋅ kg−1 ⋅ min−1for 10 min to determine uterine vasoconstrictor responses. Uterine ANG II dose-response curves were repeated following administration of the ANG II type 2 receptor (AT2) antagonist PD-123319 and then repeated again in the presence of an ANG II type 1 receptor (AT1) antagonist L-158809. In a second experiment, designed to investigate the mechanism of ANG II potentiation that occurred in the presence of AT2 blockade, nonestrogenized sheep received a uterine artery infusion of L-158809 (3 mg/min for 5 min) prior to the infusion of 0.03 μg/min of ANG II for 10 min. ANG II produced dose-dependent decreases in uterine blood flow ( P < 0.03), which were potentiated in the presence of the AT2 antagonist ( P < 0.02). Addition of the AT1 antagonist abolished the uterine vascular responses and blocked ANG II-induced increases in systemic arterial pressure ( P < 0.01). Significant uterine vasodilation ( P < 0.01) was noted with AT1 blockade in the second experiment, which was reversed by administration of the AT2 antagonist or by the nitric oxide synthetase inhibitor N ω-nitro-l-arginine methyl ester. We conclude that the AT1- receptors mediate the systemic and uterine vasoconstrictor responses to ANG II in the nonpregnant ewe. AT2-receptor blockade resulted in a potentiation of the uterine vasoconstrictor response to ANG II, suggesting that the AT2-receptor subtype may modulate uterine vascular responses to ANG II potentially by release of nitric oxide.

Angiotensin II decreases inducible nitric oxide synthase expression in rat astroglial cultures

1995 ◽  
Vol 268 (3) ◽  
pp. C700-C707 ◽  
Author(s):  
L. J. Chandler ◽  
K. Kopnisky ◽  
E. Richards ◽  
F. T. Crews ◽  
C. Sumners
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Nitric Oxide Synthase ◽  
Receptor Antagonist ◽  
Maximal Response ◽  
No Production ◽  
Dependent Manner ◽  
Ang Ii ◽  
Subsequent Formation ◽  
Oxide Synthase

Consistent with stimulation of expression of an inducible form of nitric oxide synthase (iNOS), exposure of rat astroglial cultures to lipopolysaccharide (LPS) caused a time-dependent increase in the accumulation of nitrite in the culture media. Addition of the peptide angiotensin II (ANG II) with LPS decreased subsequent formation of nitrite in a concentration-dependent manner (concentration inhibiting 50% of maximal response approximately 1 nM). The ANG II effect could be blocked by the ANG II type 1 (AT1 receptor antagonist losartan but not by the ANG II type 2 (AT2) receptor antagonist PD-123177. ANG II had no effect on nitrite formation stimulated by a combination of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma). A brief 10-min exposure to ANG II was sufficient to cause an approximately 30% inhibition of the LPS response, with maximal inhibition of approximately 65% after 3 h, and occurred only when ANG II was added during the iNOS induction phase. Consistent with partial inhibition of LPS-stimulated expression of iNOS, ANG II reduced the levels of both iNOS mRNA and iNOS protein. These results demonstrate that ANG II can decrease LPS-stimulated NO production in astroglia by inhibiting induction of iNOS expression.

Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension

1995 ◽  
Vol 269 (4) ◽  
pp. H1186-H1194 ◽  
Author(s):  
N. W. Morrell ◽  
K. G. Morris ◽  
K. R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ace Inhibition ◽  
Protective Effects ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Hypoxic Pulmonary Hypertension

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.

Chronic administration of nitric oxide reduces angiotensin II receptor type 1 expression and aldosterone synthesis in zona glomerulosa cells

2004 ◽  
Vol 287 (5) ◽  
pp. E820-E827 ◽  
Author(s):  
Kasem Nithipatikom ◽  
Blythe B. Holmes ◽  
Michael J. McCoy ◽  
Cecilia J. Hillard ◽  
William B. Campbell
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Chronic Administration ◽  
Zona Glomerulosa ◽  
Side Chain ◽  
Ang Ii ◽  
At1 Receptors ◽  
Chain Cleavage ◽  
Cleavage Enzyme

Acute nitric oxide (NO) inhibits angiotensin II (ANG II)-stimulated aldosterone synthesis in zona glomerulosa (ZG) cells. In this study, we investigated the effects of chronic administration of NO on the ANG II receptor type 1 (AT1) expression and aldosterone synthesis. ZG cells were treated daily with DETA NONOate (10−4 M), an NO donor, for 0, 12, 24, 48, 72, and 96 h. Chinese hamster ovary (CHO) cells, stably transfected with the AT1B receptor, were used as a positive control. Western blot analysis indicated that AT1 receptor expression was decreased as a function of time of NO administration in both CHO and ZG cells. ANG II binding to its receptors was determined by radioligand binding. NO treatment of ZG cells for 96 h resulted in a decrease in ANG II binding compared with control. The receptor density was decreased to 1,864 ± 129 fmol/mg protein from 3,157 ± 220 fmol/mg protein ( P < 0.005), but the affinity was not changed (1.95 ± 0.22 vs. 1.88 ± 0.21 nM). Confocal Raman microspectroscopy and immunocytochemistry both confirmed that the expression of AT1 receptors in ZG cells decreased with chronic NO administration. In addition, chronic NO administration also decreased the expression of cholesterol side-chain cleavage enzyme in ZG cells and inhibited ANG II- and 25-hydroxycholesterol-stimulated aldosterone synthesis in ZG cells. This study demonstrates that chronic administration of NO inhibits aldosterone synthesis in ZG cells by downregulation of the expression of both AT1 receptors and cholesterol side-chain cleavage enzyme.

scholarly journals Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors

2013 ◽  
Vol 304 (5) ◽  
pp. F614-F622 ◽  
Author(s):  
Daniela Patinha ◽  
Angelica Fasching ◽  
Dora Pinho ◽  
António Albino-Teixeira ◽  
Manuela Morato ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Diabetic Rats ◽  
Tubular Function ◽  
Type I ◽  
Ang Ii ◽  
Baseline Blood Pressure ◽  
Pronounced Increase ◽  
Streptozotocin Diabetic Rats ◽  
Renal Vascular

Increased angiotensin II (ANG II) or adenosine can potentiate each other in the regulation of renal hemodynamics and tubular function. Diabetes is characterized by hyperfiltration, yet the roles of ANG II and adenosine receptors for controlling baseline renal blood flow (RBF) or tubular Na+ handling in diabetes is presently unknown. Accordingly, the changes in their functions were investigated in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of the ANG II AT1 receptor antagonist candesartan, the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or their combination. Compared with controls, the baseline blood pressure, RBF, and renal vascular resistance (RVR) were similar in diabetics, whereas the glomerular filtration rate (GFR) and filtration fraction (FF) were increased. Candesartan, DPCPX, or the combination increased RBF and decreased RVR similarly in all groups. In controls, the GFR was increased by DPCPX, but in diabetics, it was decreased by candesartan. The FF was decreased by candesartan and DPCPX, independently. DPCPX caused the most pronounced increase in fractional Na+ excretion in both controls and diabetics, whereas candesartan or the combination only affected fractional Li+ excretion in diabetics. These results suggest that RBF, via a unifying mechanism, and tubular function are under strict tonic control of both ANG II and adenosine in both control and diabetic kidneys. Furthermore, increased vascular AT1 receptor activity is a contribution to diabetes-induced hyperfiltration independent of any effect of adenosine A1 receptors.

Role of 12-lipoxygenase in decreasing P-cadherin and increasing angiotensin II type 1 receptor expression according to glomerular size in type 2 diabetic rats

2011 ◽  
Vol 300 (4) ◽  
pp. E708-E716 ◽  
Author(s):  
Qiao-Yan Guo ◽  
Li-Ning Miao ◽  
Bing Li ◽  
Fu-Zhe Ma ◽  
Nian Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Diabetic Rats ◽  
Ang Ii ◽  
Direct Infusion ◽  
Protein Expressions ◽  
12 Lipoxygenase ◽  
Type 2 Diabetic

12-lipoxygenase (12-LO) was implicated in the development of diabetic nephropathy (DN), in which the proteinuria was thought to be associated with a decreased expression of glomerular P-cadherin. Therefore, we investigated the role of 12-LO in the glomerular P-cadherin expression in type 2 diabetic rats according to the glomerular sizes. Rats fed with high-fat diet for 6 wk were treated with low-dose streptozotocin. Once diabetes onset, diabetic rats were treated with 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) for 8 wk. Then glomeruli were isolated from diabetic and control rats with a sieving method. RT-PCR, Western blotting, and immunofluorescent staining were used for mRNA and protein expressions of P-cadherin and angiotensin II (Ang II) type 1 receptor (AT1). We found that CDC did not affect the glucose levels but completely attenuated diabetic increases in glomerular volume and proteinuria. Diabetes significantly decreased the P-cadherin mRNA and protein expressions and increased the AT1 mRNA and protein expressions in the glomeruli. These changes were significantly prevented by CDC and recaptured by direct infusion of 12-LO product [12(S)-HETE] to normal rats for 7 days. The decreased P-cadherin expression was similar between large and small glomeruli, but the increased AT1 expression was significantly higher in the large than in the small glomeruli from diabetic and 12(S)-HETE-treated rats. Direct infusion of normal rats with Ang II for 14 days also significantly decreased the glomerular P-cadherin expression. These results suggest that diabetic proteinuria is mediated by the activation of 12-LO pathway that is partially attributed to the decreased glomerular P-cadherin expression.

Angiotensin II receptors are expressed and functional in human esophageal mucosa

2009 ◽  
Vol 297 (5) ◽  
pp. G1019-G1027 ◽  
Author(s):  
Anna Casselbrant ◽  
Anders Edebo ◽  
Peter Hallersund ◽  
Emma Spak ◽  
Herbert F. Helander ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ion Transport ◽  
Receptor Antagonist ◽  
Ussing Chamber ◽  
Renin Angiotensin System ◽  
Esophageal Mucosa ◽  
Ang Ii

Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT1) and type 2 (AT2) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT1 and AT2 receptors. Immunoreactivity to AT1 and AT2 was localized to stratum superficiale and spinosum in the epithelium. ACE, AT1, and AT2 were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT1 receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was −6.4 mV, epithelial current ( Iep) 34 μA/cm2, and epithelial resistance ( Rep) 321 Ω·cm2. Serosal exposure to Ang II increased PD as a result of increased Iep, whereas Rep was constant. Ang II given together with the selective AT1-receptor antagonist losartan, or AT2 agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT2-receptor antagonist PD123319 did not influence PD, but Iep decreased and Rep increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT2-receptor stimulation increases epithelial ion transport, whereas the AT1 receptor inhibits ion transport and increases Rep.

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

2007 ◽  
Vol 293 (2) ◽  
pp. H1291-H1299 ◽  
Author(s):  
Amy K. L. Banes-Berceli ◽  
Pimonrat Ketsawatsomkron ◽  
Safia Ogbi ◽  
Bela Patel ◽  
David M. Pollock ◽  
...  
Keyword(s):  
Drinking Water ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Ang Ii ◽  
Endothelin 1 ◽  
Endothelium Dependent Relaxation ◽  
Stat Pathway

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [ days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT1 receptor antagonist, 10 mg·kg−1·day−1 orally in drinking water), atrasentan (ETA receptor antagonist, 10 mg·kg−1·day−1 orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg·kg−1·day−1 intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 ± 9.0, 130 ± 3.3, 128 ± 6.8, and 131 ± 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 ± 3.0, 92.6 ± 7.4, 76.9 ± 12.1, and 38.3 ± 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.

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