TGF-β impairs renal autoregulation via generation of ROS

2005 ◽  
Vol 288 (5) ◽  
pp. F1069-F1077 ◽  
Author(s):  
Kumar Sharma ◽  
Anthony Cook ◽  
Matt Smith ◽  
Cathryn Valancius ◽  
Edward W. Inscho
Keyword(s):  
Nadph Oxidase ◽  
Transforming Growth Factor ◽  
Oxidase Inhibitor ◽  
Glomerular Injury ◽  
Renal Autoregulation ◽  
Renal Vessel ◽  
Ros Scavenger ◽  
Afferent Arterioles

Impaired autoregulation in chronic kidney disease can result in elevation of glomerular capillary pressure and progressive glomerular damage; however, the factors linking chronic glomerular disorders to impaired autoregulation have not been identified. We tested the hypothesis that the cytokine most closely associated with progressive glomerular disease, transforming growth factor (TGF)-β, may also attenuate autoregulation. Kidneys from normal rats were prepared for videomicroscopy, using the blood-perfused juxtamedullary nephron technique. Autoregulatory responses were measured under control conditions and during superfusion with TGF-β1 (10 ng/ml). Control afferent arteriolar diameter averaged 18.4 ± 1 μm and significantly decreased to 16.3 ± 0.9 and 13.2 ± 0.8 μm at perfusion pressures of 130 and 160 mmHg, respectively. In the presence of TGF-β1, autoregulatory responses were completely blocked. In similar experiments performed using PDGF-BB (10 ng/ml) and HGF (25 ng/ml), the normal autoregulatory response was not affected. In vitro studies, using isolated preglomerular vascular smooth muscle cells, revealed that exposure to TGF-β1 stimulated a rapid increase in reactive oxygen species (ROS) that was inhibited by NADPH oxidase inhibitors. In situ studies, with dihydroethidium staining, revealed a marked increase in renal vessel ROS production on exposure to TGF-β1. Pretreatment of the juxtamedullary afferent arterioles with tempol, a ROS scavenger, or with apocynin, a NADPH oxidase inhibitor, prevented the impaired autoregulation induced by TGF-β1. These data reveal a novel hemodynamic pathway by which TGF-β could lead to progressive glomerular injury by impairing normal renal microvascular function.

scholarly journals Intermittent Hypoxia Affects the Spontaneous DifferentiationIn Vitroof Human Neutrophils into Long-Lived Giant Phagocytes

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Larissa Dyugovskaya ◽  
Slava Berger ◽  
Andrey Polyakov ◽  
Peretz Lavie ◽  
Lena Lavie
Keyword(s):  
Nadph Oxidase ◽  
Intermittent Hypoxia ◽  
Oxidase Inhibitor ◽  
Human Neutrophils ◽  
Hypoxic Conditions ◽  
Oxygen Conditions ◽  
Extended Lifespan ◽  
First Time ◽  
Dose Dependent

Previously we identified, for the first time, a new small-size subset of neutrophil-derived giant phagocytes (Gϕ) which spontaneously developin vitrowithout additional growth factors or cytokines. Gϕare CD66b+/CD63+/MPO+/LC3B+and are characterized by extended lifespan, large phagolysosomes, active phagocytosis, and reactive oxygen species (ROS) production, and autophagy largely controls their formation. Hypoxia, and particularly hypoxia/reoxygenation, is a prominent feature of many pathological processes. Herein we investigated Gϕformation by applying various hypoxic conditions. Chronic intermittent hypoxia (IH) (29 cycles/day for 5 days) completely abolished Gϕformation, while acute IH had dose-dependent effects. Exposure to 24 h (56 IH cycles) decreased their size, yield, phagocytic ability, autophagy, mitophagy, and gp91-phox/p22-phoxexpression, whereas under 24 h sustained hypoxia (SH) the size and expression of LC3B and gp91-phox/p22-phoxresembled Gϕformed in normoxia. Diphenyl iodide (DPI), a NADPH oxidase inhibitor, as well as the PI3K/Akt and autophagy inhibitor LY294002 abolished Gϕformation at all oxygen conditions. However, the potent antioxidant, N-acetylcysteine (NAC) abrogated the effects of IH by inducing large CD66b+/LC3B+Gϕand increased both NADPH oxidase expression and phagocytosis. These findings suggest that NADPH oxidase, autophagy, and the PI3K/Akt pathway are involved in Gϕdevelopment.

Abstract 2523: Azelnidipine Enhances Beneficial Effects of Olmesartan on Left Ventricular Remodeling During the Development of Hypertension-induced Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xian Wu Cheng ◽  
Kenji Okumura ◽  
Kohzo Nagata ◽  
Aiko Inoue ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nadph Oxidase ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Oxidase Inhibitor ◽  
List Type ◽  
Superoxide Anion Production ◽  
Cardioprotective Effects

Objective: This work was undertaken to investigate the comparative effect of angiotensin II type 1 receptor blocker (ARB) and a combination of ARB and calcium channel blocker (CCB) on left ventricular (LV) remodeling during the development of hypertensive heart failure (H-HF). Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n = 10 for each group) with vehicle, hydralazine (5 mg/kg/d), olmesartan (OLM, 5 mg/kg/d), or combined OLM and azelnidipine (AZE, 2mg/kg/d) for 8 weeks. The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins were localized in cardiac myocytes (CMCs), and Cat-dependent activities were increased by 4.1-fold in the LV of H-HF rats (n = 8, P< 0.001) and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of H-HF rats (H-HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n = 6, P< 0.0±1; control 22±2.1%). OLM suppressed not only macrophage infiltration but also levels of NADPH oxidase components (p22 phox , gp91 phox , and p47 phox ) concomitant with decreased NADPH activity and O2- production in LV tissues of H-HF rats. Along with its comparable anti-inflammatory effect, add-on AZE further improved all of these parameter changes by OLM. Furthermore, combination therapy significantly enhanced the improvement of LV fibrosis, hypertrophy, stiffness, and dysfunction by OLM. In vitro, H 2 O 2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with the antioxidants such as MnTmPyp (50 μmol/L) and N-acetylcysteine (5 mmol/L) as well as a NADPH oxidase inhibitor apocynin (100 μmol/L) in culture CMCs, SMCs, and macrophages (n = 6, P< 0.01). Conclusions: OLM and a combination of OLM and AZE exerted cardioprotective effects in hypertensive HF, via elastolytic Cat activation inhibition by the reduction of NADPH oxidase-dependent superoxide anion production. AZE enhanced the cardioprotective effects of OLM. Thus, the combination of ARB with CBB is a promising potential therapeutic strategy for H-HF.

scholarly journals Antioxidant protection by PECAM-targeted delivery of a novel NADPH-oxidase inhibitor to the endothelium in vitro and in vivo

2012 ◽  
Vol 163 (2) ◽  
pp. 161-169 ◽  
Author(s):  
Elizabeth D. Hood ◽  
Colin F. Greineder ◽  
Chandra Dodia ◽  
Jingyan Han ◽  
Clementina Mesaros ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Targeted Delivery ◽  
Oxidase Inhibitor ◽  
Antioxidant Protection ◽  
Nadph Oxidase Inhibitor

scholarly journals Dextromethorphan Reduces Oxidative Stress and Inhibits Uremic Artery Calcification

2021 ◽  
Vol 22 (22) ◽  
pp. 12277
Author(s):  
En-Shao Liu ◽  
Nai-Ching Chen ◽  
Tzu-Ming Jao ◽  
Chien-Liang Chen
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Calcification ◽  
Wistar Rats ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Oxidase Inhibitor ◽  
In Vivo Studies ◽  
Ros Production

Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium–induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium–induced VSMC calcification process (p < 0.05). The protective effect of DXM in calcified-medium–induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.

Abstract 28: Formation of Podocyte-Derived Microparticles in Diabetic Glomerular Injury

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Dylan Burger ◽  
Jean-Francois Thibodeau ◽  
Chet Holterman ◽  
Kevin D Burns ◽  
Christopher R Kennedy
Keyword(s):  
Kidney Disease ◽  
Capillary Pressure ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cyclic Stretch ◽  
Nanoparticle Tracking Analysis ◽  
Ang Ii ◽  
Glomerular Injury

Hypertension is a significant cause of progressive kidney disease, particularly in the presence of diabetes. Under such conditions, increased glomerular capillary pressure subjects podocytes, specialized glomerular epithelial cells critical to filtration, to mechanical stress resulting in podocyte injury/dysfunction. Microparticles (MPs) are small (0.1-1.0 μm), membranous vesicles shed from the cell surface following injury. However, whether podocyte MP formation reflects glomerular injury is unknown. We examined MP formation by podocytes in vitro and in vivo. Conditionally immortalized human podocytes were exposed to 10% equibiaxial cyclic stretch (a mimic of increased intraglomerular pressure), high glucose (HG, 25 mM), mannitol (osmotic control), angiotensin II (Ang II, 500 nM) or transforming growth factor beta (TGF-β, 5 ng/mL). Additionally, urinary podocyte MPs were quantified in two mouse models of diabetic kidney disease: streptozotocin (STZ) and OVE26. MPs were characterized by nanoparticle tracking analysis and quantified by Annexin V (total MPs) or podocalyxin (podocyte MPs) labeling and flow cytometry. Podocyte-derived vesicles were identifiable in both media and urine samples with a mean size of 236 nm by nanoparticle tracking analysis. In vitro, cyclic stretch was associated with a 3-fold increase in MP release after 24 hours (P<0.01, n=6). HG increased MP release 5-fold after 24 hours (P<0.05, n=6). Mannitol had no effect on MP formation by either normal or stretched podocytes and neither Ang II, nor TGF-β altered podocyte MP formation over 24 hours. In vivo, both models of diabetes displayed typical hallmarks of renal injury (proteinuria, mesangial expansion). In OVE26 mice urinary podocyte MPs were elevated compared with their wild-type littermates (17479±8329 vs. 7 ±7, P<0.05, n=5-7). Similarly, STZ-treated mice displayed increased urinary podocyte MPs as compared with untreated (18035±3813 vs. 43±34, P<0.001, n=9-18) and urinary MPs levels were positively correlated with albuminuria (r2=0.74, P<0.01). Our results suggest that podocytes produce MPs which are released into urine and are indicative of glomerular injury. Such processes may be mediated by intraglomerular capillary pressure and hyperglycemia.

Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury

2000 ◽  
Vol 279 (1) ◽  
pp. H303-H312 ◽  
Author(s):  
Jeffrey M. Dodd-O ◽  
David B. Pearse
Keyword(s):  
Lung Injury ◽  
Nadph Oxidase ◽  
Vascular Permeability ◽  
Ischemia Reperfusion ◽  
Pulmonary Artery Hypertension ◽  
Oxidase Inhibitor ◽  
Oxidase Inhibition ◽  
Pmn Leukocyte ◽  
Protein Permeability

Apocynin (4-hydroxy-3-methoxy-acetophenone) inhibits NADPH oxidase in activated polymorphonuclear (PMN) leukocytes, preventing the generation of reactive oxygen species. To determine if apocynin attenuates ischemia-reperfusion lung injury, we examined the effects of apocynin (0.03, 0.3, and 3 mM) in isolated in situ sheep lungs. In diluent-treated lungs, reperfusion with blood (180 min) after 30 min of ischemia (ventilation 28% O2, 5% CO2) caused leukocyte sequestration in the lung and increased vascular permeability [reflection coefficient for albumin (ςalb) 0.47 ± 0.10, filtration coefficient ( Kf) 0.14 ± 0.03 g · min−1· mmHg−1· 100 g−1] compared with nonreperfused lungs (ςalb0.77 ± 0.03, Kf0.03 ± 0.01 g · min−1· mmHg−1· 100 g−1; P < 0.05). Apocynin attenuated the increased protein permeability at 0.3 and 3 mM (ςalb0.69 ± 0.05 and 0.91 ± 0.03, respectively, P < 0.05); Kfwas decreased by 3 mM apocynin (0.05 ± 0.01 g · min−1· mmHg−1· 100 g−1, P < 0.05). Diphenyleneiodonium (DPI, 5 μM), a structurally unrelated inhibitor of NADPH oxidase, worsened injury ( Kf0.32 ± 0.07 g · min−1· mmHg−1· 100 g−1, P < 0.05). Neither apocynin nor DPI affected leukocyte sequestration. Apocynin and DPI inhibited whole blood chemiluminescence and isolated PMN leukocyte-induced resazurin reduction, confirming NADPH oxidase inhibition. Apocynin inhibited pulmonary artery hypertension and perfusate concentrations of cyclooxygenase metabolites, including thromboxane B2. The cyclooxygenase inhibitor indomethacin had no effect on the increased vascular permeability, suggesting that cyclooxygenase inhibition was not the explanation for the apocynin results. Apocynin prevented ischemia-reperfusion lung injury, but the mechanism of protection remains unclear.

scholarly journals Pentosan polysulfate treatment preserves renal autoregulation in ANG II-infused hypertensive rats via normalization of P2X1 receptor activation

2010 ◽  
Vol 298 (5) ◽  
pp. F1276-F1284 ◽  
Author(s):  
Zhengrong Guan ◽  
Barry S. Fuller ◽  
Tatsuo Yamamoto ◽  
Anthony K. Cook ◽  
Jennifer S. Pollock ◽  
...  
Keyword(s):  
Renal Injury ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Receptor Activation ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Pentosan Polysulfate ◽  
Hypertensive Rats ◽  
Afferent Arterioles

Inflammatory factors are elevated in animal and human subjects with hypertension and renal injury. We hypothesized that inflammation contributes to hypertension-induced renal injury by impairing autoregulation and microvascular reactivity to P2X1 receptor activation. Studies were conducted in vitro using the blood-perfused juxtamedullary nephron preparation. Rats receiving ANG II (60 ng/min) infusion were treated with the anti-inflammatory agent pentosan polysulfate (PPS) for 14 days. The magnitude and progression of hypertension were similar in ANG II and ANG II+PPS-treated rats (169 ± 5 vs. 172 ± 2 mmHg). Afferent arterioles from control rats exhibited normal autoregulatory behavior with diameter decreasing from 18.4 ± 1.6 to 11.4 ± 1.7 μm when perfusion pressure was increased from 70 to 160 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in ANG II-treated rats, and diameter remained essentially unchanged over the range of perfusion pressures. However, ANG II-treated rats receiving PPS exhibited normal autoregulatory behavior compared with ANG II alone rats. Arteriolar reactivity to ATP and β,γ-methylene ATP was significantly reduced in ANG II hypertensive rats compared with controls. Interestingly, PPS treatment preserved normal reactivity to P2 and P2X1 receptor agonists despite the persistent hypertension. The maximal vasoconstriction was 79 ± 3 and 81 ± 2% of the control diameter for ATP and β,γ-methylene ATP, respectively, similar to responses in control rats. PPS treatment significantly reduced α-smooth muscle actin staining in afferent arterioles and plasma transforming growth factor-β1 concentration in ANG II-treated rats. In conclusion, PPS normalizes autoregulation without altering ANG II-induced hypertension, suggesting that inflammatory processes reduce P2X1 receptor reactivity and thereby impair autoregulatory behavior in ANG II hypertensive rats.

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