scholarly journals Evidence for a Physiological Mitochondrial Angiotensin II System in the Kidney Proximal Tubules

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 121-132
Author(s):  
Xiao Chun Li ◽  
Xinchun Zhou ◽  
Jia Long Zhuo
Keyword(s):  
Blood Pressure ◽  
Oxygen Consumption ◽  
Angiotensin Ii ◽  
Oxygen Consumption Rate ◽  
Consumption Rate ◽  
Physiological Role ◽  
Ang Ii ◽  
Extracellular Acidification ◽  
Extracellular Acidification Rate ◽  
Mitochondria Targeting

The present study tested the hypotheses that overexpression of an intracellular Ang II (angiotensin II) fusion protein, mito-ECFP/Ang II, selectively in the mitochondria of mouse proximal tubule cells induces mitochondrial oxidative and glycolytic responses and elevates blood pressure via the Ang II/AT 1a receptor/superoxide/NHE3 (the Na + /H + exchanger 3)-dependent mechanisms. A PT-selective, mitochondria-targeting adenoviral construct encoding Ad-sglt2-mito-ECFP/Ang II was used to test the hypotheses. The expression of mito-ECFP/Ang II was colocalized primarily with Mito-Tracker Red FM in mouse PT cells or with TMRM in kidney PTs. Mito-ECFP/Ang II markedly increased oxygen consumption rate as an index of mitochondrial oxidative response (69.5%; P <0.01) and extracellular acidification rate as an index of mitochondrial glycolytic response (34%; P <0.01). The mito-ECFP/Ang II–induced oxygen consumption rate and extracellular acidification rate responses were blocked by AT 1 blocker losartan ( P <0.01) and a mitochondria-targeting superoxide scavenger mito-TEMPO ( P <0.01). By contrast, the nonselective NO inhibitor L-NAME alone increased, whereas the mitochondria-targeting expression of AT 2 receptors (mito-AT 2 /GFP) attenuated the effects of mito-ECFP/Ang II ( P <0.01). In the kidney, overexpression of mito-ECFP/Ang II in the mitochondria of the PTs increased systolic blood pressure 12±3 mm Hg ( P <0.01), and the response was attenuated in PT-specific PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Conversely, overexpression of AT 2 receptors selectively in the mitochondria of the PTs induced natriuretic responses in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Taken together, these results provide new evidence for a physiological role of PT mitochondrial Ang II/AT 1a /superoxide/NHE3 and Ang II/AT 2 /NO/NHE3 signaling pathways in maintaining blood pressure homeostasis.

scholarly journals Ceria nanoparticles ameliorate renal fibrosis by modulating the balance between oxidative phosphorylation and aerobic glycolysis

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Mengling Wang ◽  
Feng Zeng ◽  
Fengling Ning ◽  
Yinhang Wang ◽  
Shilin Zhou ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Oxygen Consumption Rate ◽  
Renal Fibrosis ◽  
Consumption Rate ◽  
Metabolic Reprogramming ◽  
Ceria Nanoparticles ◽  
Extracellular Acidification ◽  
Extracellular Acidification Rate

Abstract Background and aims Renal fibrosis is the common outcome in all progressive forms of chronic kidney disease. Unfortunately, the pathogenesis of renal fibrosis remains largely unexplored, among which metabolic reprogramming plays an extremely crucial role in the evolution of renal fibrosis. Ceria nanoparticles (CeNP-PEG) with strong ROS scavenging and anti-inflammatory activities have been applied for mitochondrial oxidative stress and inflammatory diseases. The present study aims to determine whether CeNP-PEG has therapeutic value for renal fibrosis. Methods The unilateral ureteral obstructive fibrosis model was used to assess the therapeutic effects in vivo. Transforming growth factor beta1-induced epithelial-to-mesenchymal transition in HK-2 cells was used as the in vitro cell model. The seahorse bioscience X96 extracellular flux analyzer was used to measure the oxygen consumption rate and extracellular acidification rate. Results In the present study, CeNP-PEG treatment significantly ameliorated renal fibrosis by increased E-cadherin protein expression, and decreased α-SMA, Vimentin and Fibronectin expression both in vitro and in vivo. Additionally, CeNP-PEG significantly reduced the ROS formation and improved the levels of mitochondrial ATP. The seahorse analyzer assay demonstrated that the extracellular acidification rate markedly decreased, whereas the oxygen consumption rate markedly increased, in the presence of CeNP-PEG. Furthermore, the mitochondrial membrane potential markedly enhanced, hexokinase 1 and hexokinase 2 expression significantly decreased after treatment with CeNP-PEG. Conclusions CeNP-PEG can block the dysregulated metabolic status and exert protective function on renal fibrosis. This may provide another therapeutic option for renal fibrosis. Graphical Abstract

Abstract P022: Evidence For A Physiological Mitochondrial Angiotensin Ii System In The Proximal Tubules Of The Kidney

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Xinchun Zhou ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Mitochondrial Dysfunction ◽  
Kidney Diseases ◽  
Physiological Role ◽  
Proximal Tubules ◽  
Ang Ii ◽  
New Evidence ◽  
Mitochondria Targeting

Angiotensin II (Ang II) has long been implicated in mediating mitochondrial dysfunction in cardiovascular, hypertension, and kidney diseases. However, whether it is circulating and paracrine Ang II or intracellular mitochondrial Ang II that induces mitochondrial dysfunction has not been studied previously. The present study tested the hypotheses that overexpression of an intracellular angiotensin II (Ang II) fusion protein, mito-ECFP/Ang II, selectively in the mitochondria of mouse proximal tubule (mPCT) cells induces mitochondrial oxidative and glycolytic responses and elevates blood pressure via the Ang II/AT 1a receptor/superoxide/NHE3 (the Na + /H + exchanger 3)-dependent mechanisms. A proximal tubule-selective, mitochondria-targeting adenoviral construct encoding Ad-sglt2-mito-ECFP/Ang II was used to test the hypotheses. The expression of mito-ECFP/Ang II was colocalized primarily with Mito-Tracker® Red FM in mPCT cells or with TMRM in kidney proximal tubules. mito-ECFP/Ang II markedly increased oxygen consumption rate (OCR) as an index of mitochondrial oxidative response (69.5%; P <0.01) and extracellular acidification rate (ECAR) as an index of mitochondrial glycolytic response (34%; P <0.01). The mito-ECFP/Ang II-induced OCR and ECAR responses were blocked by AT 1 blocker losartan ( P <0.01) and a mitochondria-targeting superoxide scavenger mito-TEMPO ( P <0.01). By contrast, the non-selective NO inhibitor L-NAME alone increased, whereas the mitochondria-targeting expression of AT 2 receptors (mito-AT 2 /GFP) attenuated the effects of mito-ECFP/Ang II ( P <0.01). In the kidney, overexpression of mito-ECFP/Ang II in the mitochondria of the proximal tubules increased systolic blood pressure 12 ± 3 mmHg ( P <0.01), and the response was attenuated in proximal tubule (PT)-specific PT- Agtr1a -/- and PT- Nhe3 -/- mice ( P <0.01). Conversely, overexpression of AT 2 receptors selectively in the mitochondria of the proximal tubules induced natriuretic responses in PT- Agtr1a -/- and PT- Nhe3 -/- mice ( P <0.01). Taken together, these results provide new evidence for a physiological role of proximal tubule mitochondrial Ang II/AT 1a /superoxide/NHE3 and Ang II/AT 2 /NO/NHE3 signaling pathways in maintaining blood pressure homeostasis.

Abstract 484: Multimerization of BAFF Regulates B Cell Function and Growth of Aortic Aneurysms

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Vlad Serbulea ◽  
Philipp Jakobs ◽  
Srabani Sahu ◽  
Prasad Srikakulapu ◽  
Coleen A McNamara ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
B Cells ◽  
Angiotensin Ii ◽  
B Cell ◽  
Oxygen Consumption Rate ◽  
Consumption Rate ◽  
Plasma Cells ◽  
Aortic Aneurysms ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype

B cell activating factor (BAFF) regulates differentiation and survival of B cells by binding to the surface receptors BAFF receptor (BR3), transmembrane activator and CAML interactor (TACI) and B cell maturation antigen (BCMA). During differentiation, intracellular metabolic reprogramming is crucial, such as, naïve B cells are metabolically quiescent, whereas, antibody producing plasma cells are metabolically active. We have reported that depletion of B cells protects mice from abdominal aortic aneurysm (AA), however it is not clear how B cells promote AA growth. BAFF exists as a 3mer (binds only to BR3) or as a 60mer (binds to BR3, TACI and BCMA). Therefore, we hypothesize that BAFF multimerization regulates the immune and metabolic phenotype of B cells by binding to BAFF receptors and modulate AA growth. Immunohistology was performed on AA tissues collected from patients undergoing open AA repair. Experimental AA was induced by elastase perfusion of abdominal aorta or angiotensin II infusion (1000 ng/kg/min) method in 8 weeks old male C57BL/6 or apolipoprotein E knockout mice, respectively. Western blotting, flow cytometry and Seahorse extracellular flux assays were used to determine immune and metabolic changes in B cells in response to recombinant BAFF 3mer and 60mer. BR3+ B cells were detected in the milieu of BAFF in human AAs. Mouse AAs demonstrated significant infiltration (>50/section) of CD138+ plasma B cells, but few (4-10/section) CD20+ B cells. In vitro, BAFF 3mer induced canonical NF-kB, whereas, 60mer induced both canonical and non-canonical NF-kB signaling. Moreover, the 3mer significantly decreased mitochondrial density, oxygen consumption rate, and surface expression of IgD and IgM indicating a metabolically quiescent state of B cells. However, these parameters were significantly increased by the 60mer similar to plasma cells. Anti-BR3 IgG1, but not a control IgG1 antibody decreased BAFF 60mer-induced oxygen consumption rate by 50%. In a pilot study (n=10/group), anti-BR3 IgG1, but not the control IgG1 aggravated angiotensin II-induced AA growth. Altogether, our results suggest that BAFF 3mer and 60mer oppositely regulate immune and metabolic phenotype of B cells and inhibition of BAFF-BR3 signaling is detrimental for AA growth.

Abstract P363: Annexin-A1 Deficiency Exaggerates Cardiac Remodeling In Angiotensin II-induced Hypertension

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kristy Jackson ◽  
Jaideep Singh ◽  
Yen Zhi Ng ◽  
Cheng Peng ◽  
Anida Velagic ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Physiological Role ◽  
Preclinical Model ◽  
Annexin A1 ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Induced Hypertension ◽  
Deficient Mice

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

Abstract 065: Overexpression of an Intracellular Angiotensin II Fusion Protein Selectively in the Mitochondria of the Proximal Tubules Elevates Blood Pressure in Mice via AT 1a Receptor-mediated Mitochondrial Respiratory and Glycolysis Stress

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Manoocher Soleimani ◽  
Hoang Nguyen ◽  
Hong Li ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Physiological Role ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Stress Tests ◽  
Arterial Blood ◽  
Mitochondrial Respiratory

An intracrine mitochondrial renin-angiotensin system (RAS) has recently been identified in various animal and human tissues, but whether the mitochondrial RAS plays a physiological role in the regulation of blood pressure remains unknown. The present study tested whether overexpression of an intracellular angiotensin II fusion protein, ECFP/ANG II, selectively in the mitochondria of the proximal tubules alters blood pressure, and whether the effects may involve AT 1a receptors and the Na + /H + exchanger 3 (NHE3). An adenoviral vector encoding ECFP/ANG II, a mitochondria targeting sequence, and the sglt2 promoter, Ad-sglt2-mito-ECFP/ANG II, was constructed for proximal tubule- and mitochondria-specific overexpression for 2 weeks. In adult male C57BL/6J mice, overexpression of mito-ECFP/ANG II in the mitochondria of the proximal tubules increased systolic blood pressure (SBP) significantly (Control: 116 ± 3 vs. mito-ECFP/ANG II: 128 ± 3 mmHg; p <0.01, n=15). The blood pressure-increasing effect of Ad-sglt2-mito-ECFP/ANG II was blocked in proximal tubule-specific AT 1a -KO mice (Control: 105 ± 2 vs. mito-ECFP/ANG II: 104 ± 4 mmHg; n.s ., n=7), or in proximal tubule-specific NHE3-KO mice (Control: 108 ± 3 vs. mito-ECFP/ANG II: 107 ± 3 mmHg; n.s ., n=13), respectively. In further experiments, mouse proximal tubule cells were transfected with Ad-sglt2-mito-ECFP/ANG II for 48 h and treated with the AT 1 blocker losartan (10 μM) or the AT 2 blocker PD123319 (10 μM) to measure mitochondrial respiratory and glycolytic function using Seahorse XF Cell Mito and XF Glycolysis Stress Tests. The mito-ECFP/ANG II expression was robust and colocalized with MitoTracker® Red FM. Overexpression of mito-ECFP/ANG II markedly increased oxygen consumption rate (OCR) (Control: 139.4 ± 9.2 vs. mito-ECFP/ANG II: 236.3 ± 12.6 pmol/min; p <0.01, n=12) and extracellular acidification rate (ECAR) (Control: 8.8 ± 0.6 vs. mito-ECFP/ANG II: 11.8 ± 1.2 mpH/min; p <0.01, n=12), respectively. Losartan blocked the effects of mito-ECFP/ANG II on OCR and ECAR, whereas PD123319 had no effect. We conclude that intracellular ANG II may activate AT 1 receptors in the mitochondria of the proximal tubules to alter mitochondrial respiratory and glycolytic function and arterial blood pressure.

An electronic system for cardiac and metabolic evaluation

1964 ◽  
Vol 19 (1) ◽  
pp. 153-156
Author(s):  
W. G. Kubicek ◽  
R. P. Patterson
Keyword(s):  
Blood Pressure ◽  
Oxygen Consumption ◽  
Arterial Blood Pressure ◽  
Pulse Rate ◽  
Oxygen Consumption Rate ◽  
Consumption Rate ◽  
Electronic System ◽  
Minute Volume ◽  
Arterial Blood ◽  
Expired Air

An electronic system was developed that: computes the oxygen consumption rate of a human subject while breathing room air; measures the flow rate of the expired air, expired air minute volume, tidal volume, arterial blood pressure, and pulse rate; and records the electrocardiogram. The flow rate of the expired air and the fraction concentrations of the CO2 and O2 in the expired air are measured with electronic gas analyzers and then electronically computed to give a continuous analog record of the oxygen consumption rate. All of the variables are continuously recorded in analog form. The average values of oxygen consumption rate, arterial blood pressure, or expired air minute volume and pulse rate are recorded in digital form with print out every minute. analog computer analysis of O2 consumption; continuous analog recording of expired airflow rate and minute volume, tidal volume, arterial blood pressure, and pulse rate; analog-to-digital conversion of O2 consumption, arterial blood pressure, pulse rate, and expired air minute volume; continuous recording of O2 consumption for subject breathing air; continuous electronic computation of O2 consumption Submitted on June 24, 1963

Role of splanchnic and lumbar sympathetic nerves in physiologic responses to fever and hypoxia in dogs

1959 ◽  
Vol 196 (3) ◽  
pp. 685-690
Author(s):  
W. G. Kubicek ◽  
W. F. Geber ◽  
J. W. Geiger ◽  
E. A. Johnson
Keyword(s):  
Blood Pressure ◽  
Oxygen Consumption ◽  
Lactic Acid ◽  
Blood Glucose ◽  
Pulse Rate ◽  
Oxygen Consumption Rate ◽  
Consumption Rate ◽  
Sympathetic Nerves ◽  
Blood Oxygen ◽  
Blood Ph

Induced fever up to 42°C rectal temperature produced an increase in oxygen consumption rate, plasma creatinine, blood lactic acid, hematocrit, blood oxygen content, blood pH, pulse rate, a decrease in blood sugar and a fall in blood CO2 content. Hypoxia superimposed upon the fever tended to produce an increase in blood pressure, hematocrit and pulse rate. Hypoxia probably depressed cerebral cortical activity in the unanesthetized febrile dogs. The most important function of the splanchnic and lumbar sympathetic nerves was apparently the control of the circulatory system and secondly the partial regulation of blood glucose probably through liberation of epinephrine from the adrenal medulla. A reduction in heat tolerance of the animals was observed after sympathectomy. The effects of anesthesia were apparently a reduced sensitivity of the respiratory centers and chemoreceptors. When compared to the unanesthetized experience, lower values were observed for oxygen consumption rate, blood pH, blood oxygen content, hematocrit, plasma creatinine and blood lactic acid, and in higher values for pulse rate, blood pressure, blood CO2 content and blood glucose.

scholarly journals Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

2019 ◽  
Vol 30 (5) ◽  
pp. 542-553 ◽  
Author(s):  
Dong Jun Kim ◽  
Mai-Tram Vo ◽  
Seong Hee Choi ◽  
Ji-Heon Lee ◽  
So Yeon Jeong ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Oxygen Consumption Rate ◽  
Consumption Rate ◽  
Ectopic Expression ◽  
Mrna Degradation ◽  
Negative Regulator ◽  
Extracellular Acidification ◽  
Hexokinase 2

Hexokinase 2 (HK2) catalyzes the first step of glycolysis and is up-regulated in cancer cells. The mechanism has not been fully elucidated. Tristetraprolin (TTP) is an AU-rich element (ARE)-binding protein that inhibits the expression of ARE-containing genes by enhancing mRNA degradation. TTP expression is down-regulated in cancer cells. We demonstrated that TTP is critical for down-regulation of HK2 expression in cancer cells. HK2 mRNA contains an ARE within its 3′-UTR. TTP binds to HK2 3′-UTR and enhances degradation of HK2 mRNA. TTP overexpression decreased HK2 expression and suppressed the glycolytic capacity of cancer cells, measured as glucose uptake and production of glucose-6-phosphate, pyruvate, and lactate. TTP overexpression reduced both the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) of cancer cells. Ectopic expression of HK2 in cancer cells attenuated the reduction in glycolytic capacity, ECAR, and OCR from TTP. Taken together, these findings suggest that TTP acts as a negative regulator of HK2 expression and glucose metabolism in cancer cells.

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