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Christopher S Wilcox - One of the best experts on this subject based on the ideXlab platform.
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high salt enhances reactive oxygen species and angiotensin ii contractions of glomerular Afferent Arterioles from mice with reduced renal mass
Hypertension, 2018Co-Authors: En Yin Lai, Anton Wellstein, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Margarida Mendonca, Christopher S WilcoxAbstract:High salt, Ang II (angiotensin II), and reactive oxygen species enhance progression of chronic kidney disease. We tested the hypothesis that a high salt intake generates specific reactive oxygen species to enhance Ang II contractions of Afferent Arterioles from mice with reduced renal mass (RRM). C57BL/6 mice were subjected to surgical RRM or sham operations and received 6% or 0.4% NaCl salt diet for 3 months. Ang II contractions were measured in perfused Afferent Arterioles and superoxide (O2-) and hydrogen peroxide (H2O2) by fluorescence microscopy. RRM enhanced the Afferent arteriolar gene expression for p47phox and neutrophil oxidase (NOX) 2 and high salt intake in RRM mice enhanced gene expression for angiotensin type 1 receptors, POLDIP2 and NOX4 and reduced catalase. High salt in mice with RRM enhanced arteriolar O2- and H2O2 generation and maximal contractions to Ang II (10-6 mol/L) that were dependent on O2- because they were prevented by gene deletion of p47phox and on H2O2 because they were prevented by transgenic smooth muscle cell expression of catalase (tgCAT-SMC) and POLDIP2 gene deletion. Three months of tempol normalized arteriolar reactive oxygen species and Ang II contractions. However, arteriolar contractions to lower concentrations of Ang II (10-8 to 10-11 mol/L) were paradoxically inhibited by H2O2 and POLDIP2. In conclusion, both O2- from p47phox/NOX2 and H2O2 from NOX4/POLDIP2 enhance maximal arteriolar Ang II contractions from RRM mice during high salt, but H2O2 and NOX4/POLDIP2 reduce the sensitivity to lower concentrations of Ang II by >100-fold. Tempol prevents all of these changes in function.
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superoxide and hydrogen peroxide counterregulate myogenic contractions in renal Afferent Arterioles from a mouse model of chronic kidney disease
Kidney International, 2017Co-Authors: En Yin Lai, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Robert W Taylor, Pedro A Jose, Anton Wellsten, Christopher S WilcoxAbstract:Myogenic contractions protect kidneys from barotrauma but are impaired in chronic kidney disease (CKD). Since myogenic contractions are enhanced by superoxide but impaired by hydrogen peroxide, we tested the hypothesis that they are counterregulated by superoxide and H 2 O 2 from NOX2/p47phox and/or NOX4/POLDIP2 in CKD. Myogenic contraction in isolated perfused Afferent Arterioles from mice with surgical 5/6 nephrectomy or sham operations fed a 6% sodium chloride diet was measured directly while superoxide and H 2 O 2 were measured by fluorescence microscopy. Compared to sham-operated animals, an increase in perfusion pressure of Arterioles from CKD mice doubled superoxide (21 versus 11%), increased H 2 O 2 seven-fold (29 versus 4%), and reduced myogenic contractions profoundly (-1 versus -14%). Myogenic contractions were impaired further by PEG-superoxide dismutase or in Arterioles from p47phox-/- (versus wild type) mice but became supra-normal by PEG-catalase or in mice with transgenic expression of catalase in vascular smooth muscle cells (-11 versus -1%). Single Arterioles from mice with CKD expressed over 40% more mRNA and protein for NOX4 and POLDIP2. Myogenic responses in Arterioles from POLDIP2 +/- (versus wild type) mice with CKD had over an 85% reduction in H 2 O 2 , but preserved superoxide and a normal myogenic response. Tempol administration to CKD mice for 3 months decreased Afferent arteriolar superoxide and H 2 O 2 and maintained myogenic contractions. Thus, Afferent arteriolar superoxide generated by NOX2/p47phox opposes H 2 O 2 generated by NOX4/POLDIP2 whose upregulation in Afferent Arterioles from mice with CKD accounts for impaired myogenic contractions.
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Increased hydrogen peroxide impairs angiotensin II contractions of Afferent Arterioles in mice after renal ischaemia-reperfusion injury.
Acta physiologica (Oxford England), 2016Co-Authors: Qian Huang, Andreas Patzak, Qiaoling Wang, Suping Zhang, Shan Jiang, Liang Zhao, Michael Hultström, Christopher S WilcoxAbstract:AIM Renal ischaemia-reperfusion injury (IRI) increases angiotensin II (Ang II) and reactive oxygen species (ROS) that are potent modulators of vascular function. However, the roles of individual ROS and their interaction with Ang II are not clear. Here we tested the hypothesis that IRI modulates renal Afferent arteriolar responses to Ang II via increasing superoxide (O2-) or hydrogen peroxide (H2 O2 ). METHODS Renal Afferent Arterioles were isolated and perfused from C57BL/6 mice 24 h after IRI or sham surgery. Responses to Ang II or noradrenaline were assessed by measuring arteriolar diameter. Production of H2 O2 and O2- was assessed in Afferent Arterioles and renal cortex. Activity of SOD and catalase, and mRNA expressions of Ang II receptors were assessed in pre-glomerular Arterioles and renal cortex. RESULTS Afferent Arterioles from mice after IRI had a reduced maximal contraction to Ang II (-27±2 vs. -42±1%, P
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increased hydrogen peroxide impairs angiotensin ii contractions of Afferent Arterioles in mice after renal ischaemia reperfusion injury
Acta Physiologica, 2016Co-Authors: Qian Huang, Christopher S Wilcox, Andreas Patzak, Qiaoling Wang, Suping Zhang, Shan Jiang, Liang Zhao, Michael Hultström, En Yin LaiAbstract:AIM Renal ischaemia-reperfusion injury (IRI) increases angiotensin II (Ang II) and reactive oxygen species (ROS) that are potent modulators of vascular function. However, the roles of individual ROS and their interaction with Ang II are not clear. Here we tested the hypothesis that IRI modulates renal Afferent arteriolar responses to Ang II via increasing superoxide (O2-) or hydrogen peroxide (H2 O2 ). METHODS Renal Afferent Arterioles were isolated and perfused from C57BL/6 mice 24 h after IRI or sham surgery. Responses to Ang II or noradrenaline were assessed by measuring arteriolar diameter. Production of H2 O2 and O2- was assessed in Afferent Arterioles and renal cortex. Activity of SOD and catalase, and mRNA expressions of Ang II receptors were assessed in pre-glomerular Arterioles and renal cortex. RESULTS Afferent Arterioles from mice after IRI had a reduced maximal contraction to Ang II (-27±2 vs. -42±1%, P < 0.001), but retained a normal contraction to noradrenaline. Arterioles after IRI had a 38% increase in H2 O2 (P < 0.001) and a 45% decrease in catalase activity (P < 0.01). Contractions were reduced in normal Arterioles after incubation with H2 O2 (-22±2 vs. -42±1%, P < 0.05) similar to the effects of IRI. However, the impaired contractions were normalized by incubation with PEG catalase despite a reduced AT1 R expression. CONCLUSIONS Renal IRI in mice selectively impairs Afferent arteriolar responses to Ang II because of H2 O2 accumulation that is caused by a reduced catalase activity. This could serve to buffer the effect of Ang II after IRI and may be a protective mechanism.
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differential effects of superoxide and hydrogen peroxide on myogenic signaling membrane potential and contractions of mouse renal Afferent Arterioles
American Journal of Physiology-renal Physiology, 2016Co-Authors: En Yin Lai, Anton Wellstein, William J Welch, Christopher S WilcoxAbstract:Myogenic contraction is the principal component of renal autoregulation that protects the kidney from hypertensive barotrauma. Contractions are initiated by a rise in perfusion pressure that signals a reduction in membrane potential (Em) of vascular smooth muscle cells to activate voltage-operated Ca(2+) channels. Since ROS have variable effects on myogenic tone, we investigated the hypothesis that superoxide (O2 (·-)) and H2O2 differentially impact myogenic contractions. The myogenic contractions of mouse isolated and perfused single Afferent Arterioles were assessed from changes in luminal diameter with increasing perfusion pressure (40-80 mmHg). O2 (·-), H2O2, and Em were assessed by fluorescence microscopy during incubation with paraquat to increase O2 (·-) or with H2O2 Paraquat enhanced O2 (·-) generation and myogenic contractions (-42 ± 4% vs. -19 ± 4%, P < 0.005) that were blocked by SOD but not by catalase and signaled via PKC. In contrast, H2O2 inhibited the effects of paraquat and reduced myogenic contractions (-10 ± 1% vs. -19 ± 2%, P < 0.005) and signaled via PKG. O2 (·-) activated Ca(2+)-activated Cl(-) channels that reduced Em, whereas H2O2 activated Ca(2+)-activated and voltage-gated K(+) channels that increased Em Blockade of voltage-operated Ca(2+) channels prevented the enhanced myogenic contractions with paraquat without preventing the reduction in Em Myogenic contractions were independent of the endothelium and largely independent of nitric oxide. We conclude that O2 (·-) and H2O2 activate different signaling pathways in vascular smooth muscle cells linked to discreet membrane channels with opposite effects on Em and voltage-operated Ca(2+) channels and therefore have opposite effects on myogenic contractions.
En Yin Lai - One of the best experts on this subject based on the ideXlab platform.
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high salt enhances reactive oxygen species and angiotensin ii contractions of glomerular Afferent Arterioles from mice with reduced renal mass
Hypertension, 2018Co-Authors: En Yin Lai, Anton Wellstein, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Margarida Mendonca, Christopher S WilcoxAbstract:High salt, Ang II (angiotensin II), and reactive oxygen species enhance progression of chronic kidney disease. We tested the hypothesis that a high salt intake generates specific reactive oxygen species to enhance Ang II contractions of Afferent Arterioles from mice with reduced renal mass (RRM). C57BL/6 mice were subjected to surgical RRM or sham operations and received 6% or 0.4% NaCl salt diet for 3 months. Ang II contractions were measured in perfused Afferent Arterioles and superoxide (O2-) and hydrogen peroxide (H2O2) by fluorescence microscopy. RRM enhanced the Afferent arteriolar gene expression for p47phox and neutrophil oxidase (NOX) 2 and high salt intake in RRM mice enhanced gene expression for angiotensin type 1 receptors, POLDIP2 and NOX4 and reduced catalase. High salt in mice with RRM enhanced arteriolar O2- and H2O2 generation and maximal contractions to Ang II (10-6 mol/L) that were dependent on O2- because they were prevented by gene deletion of p47phox and on H2O2 because they were prevented by transgenic smooth muscle cell expression of catalase (tgCAT-SMC) and POLDIP2 gene deletion. Three months of tempol normalized arteriolar reactive oxygen species and Ang II contractions. However, arteriolar contractions to lower concentrations of Ang II (10-8 to 10-11 mol/L) were paradoxically inhibited by H2O2 and POLDIP2. In conclusion, both O2- from p47phox/NOX2 and H2O2 from NOX4/POLDIP2 enhance maximal arteriolar Ang II contractions from RRM mice during high salt, but H2O2 and NOX4/POLDIP2 reduce the sensitivity to lower concentrations of Ang II by >100-fold. Tempol prevents all of these changes in function.
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glucose dilates renal Afferent Arterioles via glucose transporter 1
American Journal of Physiology-renal Physiology, 2018Co-Authors: Jie Zhang, En Yin Lai, Shan Jiang, Jin Wei, Kaypong Yip, Lei Wang, Ruisheng LiuAbstract:Glomerular hyperfiltration often occurs during the early stage of diabetes. An acute glucose infusion increases glomerular filtration rate (GFR). The involvement of tubuloglomerular feedback response and direct effect of glucose on the Afferent Arterioles (Af-Arts) have been suggested. However, the signaling pathways to trigger Af-Art dilatation have not been fully identified. Therefore, in the present study we tested our hypothesis that an increase of glucose concentration enhances endothelial nitric oxide synthesis (NOS3) activity and dilates the Af-Arts via glucose transporter 1 (GLUT1) using isolated mouse Af-Arts with perfusion. We isolated and microperfused the Af-Arts from non-diabetic C57BL/6 mice. The Af-Arts were preconstricted with norepinephrine (NE, 1 µM). When we switched the D-glucose concentration from low (5 mM) to high (30 mM) in the perfusate, the preconstricted Af-Arts significantly dilated by 37.8{plus minus}7.1%, but L-glucose did not trigger the dilation. GLUT1 mRNA was identified i...
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superoxide and hydrogen peroxide counterregulate myogenic contractions in renal Afferent Arterioles from a mouse model of chronic kidney disease
Kidney International, 2017Co-Authors: En Yin Lai, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Robert W Taylor, Pedro A Jose, Anton Wellsten, Christopher S WilcoxAbstract:Myogenic contractions protect kidneys from barotrauma but are impaired in chronic kidney disease (CKD). Since myogenic contractions are enhanced by superoxide but impaired by hydrogen peroxide, we tested the hypothesis that they are counterregulated by superoxide and H 2 O 2 from NOX2/p47phox and/or NOX4/POLDIP2 in CKD. Myogenic contraction in isolated perfused Afferent Arterioles from mice with surgical 5/6 nephrectomy or sham operations fed a 6% sodium chloride diet was measured directly while superoxide and H 2 O 2 were measured by fluorescence microscopy. Compared to sham-operated animals, an increase in perfusion pressure of Arterioles from CKD mice doubled superoxide (21 versus 11%), increased H 2 O 2 seven-fold (29 versus 4%), and reduced myogenic contractions profoundly (-1 versus -14%). Myogenic contractions were impaired further by PEG-superoxide dismutase or in Arterioles from p47phox-/- (versus wild type) mice but became supra-normal by PEG-catalase or in mice with transgenic expression of catalase in vascular smooth muscle cells (-11 versus -1%). Single Arterioles from mice with CKD expressed over 40% more mRNA and protein for NOX4 and POLDIP2. Myogenic responses in Arterioles from POLDIP2 +/- (versus wild type) mice with CKD had over an 85% reduction in H 2 O 2 , but preserved superoxide and a normal myogenic response. Tempol administration to CKD mice for 3 months decreased Afferent arteriolar superoxide and H 2 O 2 and maintained myogenic contractions. Thus, Afferent arteriolar superoxide generated by NOX2/p47phox opposes H 2 O 2 generated by NOX4/POLDIP2 whose upregulation in Afferent Arterioles from mice with CKD accounts for impaired myogenic contractions.
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Extravasal albumin concentration modulates contractile responses of renal Afferent Arterioles
Acta physiologica (Oxford England), 2017Co-Authors: Xiang Gao, En Yin Lai, Zhi Zhao Liu, H. Mohammed, Diana Braun, Zhengbing Zhuge, Ming Liu, Leif Jansson, Mattias Carlström, Andreas PatzakAbstract:AIM Afferent Arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback, the Afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates Afferent arteriolar tone, a mechanism which may contribute to body fluid volume control. METHOD The effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, in rat renal AA and in pancreatic islet Arterioles. RESULTS Albumin (2 and 4% in the bath solution) significantly potentiated the contractile response of renal Afferent Arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet Arterioles. Mimicking the increase in the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal Arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in Afferent Arterioles exposed to 4% albumin. CONCLUSION The protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.
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Myoglobin facilitates angiotensin II induced constriction of renal Afferent Arterioles
American journal of physiology. Renal physiology, 2017Co-Authors: Zhi Zhao Liu, En Yin Lai, Susanne Mathia, Tamara Margit Jutta Pahlitzsch, Inggrid Christine Wennysia, Pontus B. Persson, Anica Högner, Rudolf Schubert, Christian RosenbergerAbstract:Vasoconstriction plays an important role in the development of acute kidney injury in rhabdomyolysis. We hypothesized that myoglobin enhances the angiotensin II (ANG II) response in Afferent Arterioles by increasing superoxide and reducing nitric oxide (NO) bioavailability. Afferent Arterioles of C57Bl6 mice were isolated perfused, and vasoreactivity was analyzed using video microscopy. NO bioavailability, superoxide concentration in the vessel wall, and changes in cytosolic calcium were measured using fluorescence techniques. Myoglobin treatment (10-5 M) did not change the basal arteriolar diameter during a 20-min period compared with control conditions. NG-nitro-l-arginine methyl ester (l-NAME, 10-4 M) and l-NAME + myoglobin reduced diameters to 94.7 and 97.9% of the initial diameter, respectively. Myoglobin or l-NAME enhanced the ANG II-induced constriction of Arterioles compared with control (36.6 and 34.2%, respectively, vs. 65.9%). Norepinephrine responses were not influenced by myoglobin. Combined application of myoglobin and l-NAME further facilitated the ANG II response (7.0%). Myoglobin or l-NAME decreased the NO-related fluorescence in Arterioles similarly. Myoglobin enhanced the superoxide-related fluorescence, and tempol prevented this enhancement. Tempol also partly prevented the myoglobin effect on the ANG II response. Myoglobin increased the fura 2 fluorescence ratio (cytosolic calcium) during ANG II application (10-12 to 10-6 M). The results suggest that the enhanced Afferent arteriolar reactivity to ANG II is mainly due to a myoglobin-induced increase in superoxide and associated reduction in the NO bioavailability. Signaling pathways for the augmented ANG II response include enhanced cytosolic calcium transients. In conclusion, myoglobin may contribute to the Afferent arteriolar vasoconstriction in this rhabdomyolysis model.
Andreas Patzak - One of the best experts on this subject based on the ideXlab platform.
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Extravasal albumin concentration modulates contractile responses of renal Afferent Arterioles
Acta physiologica (Oxford England), 2017Co-Authors: Xiang Gao, En Yin Lai, Zhi Zhao Liu, H. Mohammed, Diana Braun, Zhengbing Zhuge, Ming Liu, Leif Jansson, Mattias Carlström, Andreas PatzakAbstract:AIM Afferent Arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback, the Afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates Afferent arteriolar tone, a mechanism which may contribute to body fluid volume control. METHOD The effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, in rat renal AA and in pancreatic islet Arterioles. RESULTS Albumin (2 and 4% in the bath solution) significantly potentiated the contractile response of renal Afferent Arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet Arterioles. Mimicking the increase in the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal Arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in Afferent Arterioles exposed to 4% albumin. CONCLUSION The protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.
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Increased hydrogen peroxide impairs angiotensin II contractions of Afferent Arterioles in mice after renal ischaemia-reperfusion injury.
Acta physiologica (Oxford England), 2016Co-Authors: Qian Huang, Andreas Patzak, Qiaoling Wang, Suping Zhang, Shan Jiang, Liang Zhao, Michael Hultström, Christopher S WilcoxAbstract:AIM Renal ischaemia-reperfusion injury (IRI) increases angiotensin II (Ang II) and reactive oxygen species (ROS) that are potent modulators of vascular function. However, the roles of individual ROS and their interaction with Ang II are not clear. Here we tested the hypothesis that IRI modulates renal Afferent arteriolar responses to Ang II via increasing superoxide (O2-) or hydrogen peroxide (H2 O2 ). METHODS Renal Afferent Arterioles were isolated and perfused from C57BL/6 mice 24 h after IRI or sham surgery. Responses to Ang II or noradrenaline were assessed by measuring arteriolar diameter. Production of H2 O2 and O2- was assessed in Afferent Arterioles and renal cortex. Activity of SOD and catalase, and mRNA expressions of Ang II receptors were assessed in pre-glomerular Arterioles and renal cortex. RESULTS Afferent Arterioles from mice after IRI had a reduced maximal contraction to Ang II (-27±2 vs. -42±1%, P
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increased hydrogen peroxide impairs angiotensin ii contractions of Afferent Arterioles in mice after renal ischaemia reperfusion injury
Acta Physiologica, 2016Co-Authors: Qian Huang, Christopher S Wilcox, Andreas Patzak, Qiaoling Wang, Suping Zhang, Shan Jiang, Liang Zhao, Michael Hultström, En Yin LaiAbstract:AIM Renal ischaemia-reperfusion injury (IRI) increases angiotensin II (Ang II) and reactive oxygen species (ROS) that are potent modulators of vascular function. However, the roles of individual ROS and their interaction with Ang II are not clear. Here we tested the hypothesis that IRI modulates renal Afferent arteriolar responses to Ang II via increasing superoxide (O2-) or hydrogen peroxide (H2 O2 ). METHODS Renal Afferent Arterioles were isolated and perfused from C57BL/6 mice 24 h after IRI or sham surgery. Responses to Ang II or noradrenaline were assessed by measuring arteriolar diameter. Production of H2 O2 and O2- was assessed in Afferent Arterioles and renal cortex. Activity of SOD and catalase, and mRNA expressions of Ang II receptors were assessed in pre-glomerular Arterioles and renal cortex. RESULTS Afferent Arterioles from mice after IRI had a reduced maximal contraction to Ang II (-27±2 vs. -42±1%, P < 0.001), but retained a normal contraction to noradrenaline. Arterioles after IRI had a 38% increase in H2 O2 (P < 0.001) and a 45% decrease in catalase activity (P < 0.01). Contractions were reduced in normal Arterioles after incubation with H2 O2 (-22±2 vs. -42±1%, P < 0.05) similar to the effects of IRI. However, the impaired contractions were normalized by incubation with PEG catalase despite a reduced AT1 R expression. CONCLUSIONS Renal IRI in mice selectively impairs Afferent arteriolar responses to Ang II because of H2 O2 accumulation that is caused by a reduced catalase activity. This could serve to buffer the effect of Ang II after IRI and may be a protective mechanism.
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nitric oxide deficiency and increased adenosine response of Afferent Arterioles in hydronephrotic mice with hypertension
Hypertension, 2008Co-Authors: Mattias Carlström, En Yin Lai, Andreas Patzak, Andreas Steege, Mauricio Sendeski, Sheller Zabihi, Ulf J Eriksson, Erik A G PerssonAbstract:Afferent Arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused Arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N(G)-nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (-6%) but reduced it in control (-12%) and contralateral Arterioles (-43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic Arterioles (-18%) than in control (-42%) and contralateral Arterioles (-49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (-19%) compared with control (-8%) and contralateral kidneys (+/-0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral Arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic Arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (-40%) was observed for all of the groups. This response was totally abolished in Arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension.
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angiotensin ii response in Afferent Arterioles of mice lacking either the endothelial or neuronal isoform of nitric oxide synthase
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2008Co-Authors: Andreas Patzak, En Yin Lai, Andreas Steege, Jan Ole Brinkmann, Eckehardt Kupsch, Nadine Spielmann, Adrian Gericke, Angela Skalweit, Johannes Stegbauer, Pontus B. PerssonAbstract:The aim of the study is to evaluate the impact of nitric oxide (NO) produced by endothelial NO synthase (eNOS) and neuronal NOS (nNOS) on the angiotensin II response in Afferent Arterioles (Af). Do...
William J Welch - One of the best experts on this subject based on the ideXlab platform.
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high salt enhances reactive oxygen species and angiotensin ii contractions of glomerular Afferent Arterioles from mice with reduced renal mass
Hypertension, 2018Co-Authors: En Yin Lai, Anton Wellstein, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Margarida Mendonca, Christopher S WilcoxAbstract:High salt, Ang II (angiotensin II), and reactive oxygen species enhance progression of chronic kidney disease. We tested the hypothesis that a high salt intake generates specific reactive oxygen species to enhance Ang II contractions of Afferent Arterioles from mice with reduced renal mass (RRM). C57BL/6 mice were subjected to surgical RRM or sham operations and received 6% or 0.4% NaCl salt diet for 3 months. Ang II contractions were measured in perfused Afferent Arterioles and superoxide (O2-) and hydrogen peroxide (H2O2) by fluorescence microscopy. RRM enhanced the Afferent arteriolar gene expression for p47phox and neutrophil oxidase (NOX) 2 and high salt intake in RRM mice enhanced gene expression for angiotensin type 1 receptors, POLDIP2 and NOX4 and reduced catalase. High salt in mice with RRM enhanced arteriolar O2- and H2O2 generation and maximal contractions to Ang II (10-6 mol/L) that were dependent on O2- because they were prevented by gene deletion of p47phox and on H2O2 because they were prevented by transgenic smooth muscle cell expression of catalase (tgCAT-SMC) and POLDIP2 gene deletion. Three months of tempol normalized arteriolar reactive oxygen species and Ang II contractions. However, arteriolar contractions to lower concentrations of Ang II (10-8 to 10-11 mol/L) were paradoxically inhibited by H2O2 and POLDIP2. In conclusion, both O2- from p47phox/NOX2 and H2O2 from NOX4/POLDIP2 enhance maximal arteriolar Ang II contractions from RRM mice during high salt, but H2O2 and NOX4/POLDIP2 reduce the sensitivity to lower concentrations of Ang II by >100-fold. Tempol prevents all of these changes in function.
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superoxide and hydrogen peroxide counterregulate myogenic contractions in renal Afferent Arterioles from a mouse model of chronic kidney disease
Kidney International, 2017Co-Authors: En Yin Lai, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Robert W Taylor, Pedro A Jose, Anton Wellsten, Christopher S WilcoxAbstract:Myogenic contractions protect kidneys from barotrauma but are impaired in chronic kidney disease (CKD). Since myogenic contractions are enhanced by superoxide but impaired by hydrogen peroxide, we tested the hypothesis that they are counterregulated by superoxide and H 2 O 2 from NOX2/p47phox and/or NOX4/POLDIP2 in CKD. Myogenic contraction in isolated perfused Afferent Arterioles from mice with surgical 5/6 nephrectomy or sham operations fed a 6% sodium chloride diet was measured directly while superoxide and H 2 O 2 were measured by fluorescence microscopy. Compared to sham-operated animals, an increase in perfusion pressure of Arterioles from CKD mice doubled superoxide (21 versus 11%), increased H 2 O 2 seven-fold (29 versus 4%), and reduced myogenic contractions profoundly (-1 versus -14%). Myogenic contractions were impaired further by PEG-superoxide dismutase or in Arterioles from p47phox-/- (versus wild type) mice but became supra-normal by PEG-catalase or in mice with transgenic expression of catalase in vascular smooth muscle cells (-11 versus -1%). Single Arterioles from mice with CKD expressed over 40% more mRNA and protein for NOX4 and POLDIP2. Myogenic responses in Arterioles from POLDIP2 +/- (versus wild type) mice with CKD had over an 85% reduction in H 2 O 2 , but preserved superoxide and a normal myogenic response. Tempol administration to CKD mice for 3 months decreased Afferent arteriolar superoxide and H 2 O 2 and maintained myogenic contractions. Thus, Afferent arteriolar superoxide generated by NOX2/p47phox opposes H 2 O 2 generated by NOX4/POLDIP2 whose upregulation in Afferent Arterioles from mice with CKD accounts for impaired myogenic contractions.
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differential effects of superoxide and hydrogen peroxide on myogenic signaling membrane potential and contractions of mouse renal Afferent Arterioles
American Journal of Physiology-renal Physiology, 2016Co-Authors: En Yin Lai, Anton Wellstein, William J Welch, Christopher S WilcoxAbstract:Myogenic contraction is the principal component of renal autoregulation that protects the kidney from hypertensive barotrauma. Contractions are initiated by a rise in perfusion pressure that signals a reduction in membrane potential (Em) of vascular smooth muscle cells to activate voltage-operated Ca(2+) channels. Since ROS have variable effects on myogenic tone, we investigated the hypothesis that superoxide (O2 (·-)) and H2O2 differentially impact myogenic contractions. The myogenic contractions of mouse isolated and perfused single Afferent Arterioles were assessed from changes in luminal diameter with increasing perfusion pressure (40-80 mmHg). O2 (·-), H2O2, and Em were assessed by fluorescence microscopy during incubation with paraquat to increase O2 (·-) or with H2O2 Paraquat enhanced O2 (·-) generation and myogenic contractions (-42 ± 4% vs. -19 ± 4%, P < 0.005) that were blocked by SOD but not by catalase and signaled via PKC. In contrast, H2O2 inhibited the effects of paraquat and reduced myogenic contractions (-10 ± 1% vs. -19 ± 2%, P < 0.005) and signaled via PKG. O2 (·-) activated Ca(2+)-activated Cl(-) channels that reduced Em, whereas H2O2 activated Ca(2+)-activated and voltage-gated K(+) channels that increased Em Blockade of voltage-operated Ca(2+) channels prevented the enhanced myogenic contractions with paraquat without preventing the reduction in Em Myogenic contractions were independent of the endothelium and largely independent of nitric oxide. We conclude that O2 (·-) and H2O2 activate different signaling pathways in vascular smooth muscle cells linked to discreet membrane channels with opposite effects on Em and voltage-operated Ca(2+) channels and therefore have opposite effects on myogenic contractions.
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abstract 060 poldip 2 nox 4 generates hydrogen peroxide that impairs myogenic response of Afferent Arterioles from mice with the reduced renal mass model of chronic kidney disease
Hypertension, 2015Co-Authors: En Yin Lai, William J Welch, Glenn Solis, Zaiming Luo, Kathy K Griendling, Robert W Taylor, Wilcox S ChristopherAbstract:Background: Because we have found that myogenic contractions are stimulated by superoxide (O 2 .- ) but inhibited by hydrogen peroxide (H 2 O 2 ), we tested the hypothesis that H 2 O 2 is the cause of the impaired myogenic responses of Afferent Arterioles from mice with the reduced renal mass (RRM) model of chronic kidney disease (CKD). Methods: Mice were subjected to 5/6 surgical nephrectomy or sham operations and fed 6% salt for 3 months. Single Afferent Arterioles were perfused, their diameter measured directly and O 2 .- and H 2 O 2 measured by fluorescence microscopy. Results: The perfusion pressure of isolated Afferent Arterioles was increased from 40 to 80 mmHg to study myogenic responses. Arterioles from mice with RRM (vs sham) had a greater increase in O 2 .- (21.2 ± 1.9 versus 11.3 ± 2.5%; p 2 O 2 (28.7 ± 3.7 versus 4.2 ± 0.4%, P 2 .- by PEG-SOD (+3.3 ± 1.5 versus -1.7 ± 4.3%, P phox (+2.5 ± 1.4 versus -1.7 ± 4.3%, P 2 O 2 by PEG-catalase (-19.1 ± 1.6 versus -1.7 ± 4.3%, P 2 O 2 ) was increased 40-50% (P Conclusions: Afferent Arterioles from mice with RRM had severely impaired myogenic responses that were attributed to increased H 2 O 2 generation from POLDIP-2/NOX-4 that may therefore be novel targets to maintain autoregulation and protect kidneys from barotrauma in CKD.
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remodeling of Afferent Arterioles from mice with oxidative stress does not account for increased contractility but does limit excessive wall stress
Hypertension, 2015Co-Authors: Di Feng, Christopher S Wilcox, William J Welch, Zaiming Luo, En Yin LaiAbstract:Because superoxide dismutase (SOD) knockout enhances arteriolar remodeling and contractility, we hypothesized that remodeling enhances contractility. In the isolated and perfused renal Afferent Arterioles from SOD wild type (+/+) and gene-deleted mice, contractility was assessed from reductions in luminal diameter with perfusion pressure from 40 to 80 mm Hg (myogenic responses) or angiotensin II (10 –6 mol/L), remodeling from media:lumen area ratio, superoxide (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ) from fluorescence microscopy, and wall stress from wall tension/wall thickness. Compared with +/+ strains, Arterioles from SOD1−/−, SOD2+/−, and SOD3−/− mice developed significantly ( P 2 ·− with perfusion pressure and angiotensin II and significantly increased myogenic responses (SOD1−/−: −20.7±2.2% versus −12.7±1.6%; SOD2+/−: −7.4±1.3% versus −12.6±1.4%; and SOD3−/−: −9.1±1.9% versus −15.8±2.2%) and angiotensin II contractions and ≈2-fold increased media:lumen ratios. Media:lumen ratios correlated with myogenic responses ( r 2 =0.23; P r 2 =0.57; P r 2 =0.19; P r 2 =0.08; NS). Differences in myogenic responses among SOD3 mice were abolished by bath addition of SOD and were increased 3 days after inducing SOD3 knockout (−26.9±1.7% versus −20.1±0.7%; P 2 ·− enhance Afferent arteriolar contractility and remodeling. Although remodeling does not enhance contractility, it does prevent the potentially damaging effects of increased wall stress.
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Effects of angiotensin II on isolated rabbit Afferent Arterioles.
Japanese Journal of Pharmacology, 2019Co-Authors: Hiroyuki Yoshida, Toshiaki Tamaki, Shoji Kimura, Ikumasa TakenakaAbstract:We examined the effects of angiotensin II (Ang II) on isolated rabbit Afferent Arterioles to assess the direct effect of Ang II at the resistance vessel level in the kidney. We microdissected the superficial Afferent arteriole from the kidney of New Zealand White rabbits. The Afferent arteriole was cannulated with a micropipette system, and the intraluminal pressure was set at 80 mmHg. Ang II did not change the lumen diameter of the Afferent Arterioles. After the Afferent Arterioles were pretreated with aspirin DL-lysine or indomethacin, Ang II (10-7 M) caused transient vasoconstriction in the Afferent Arterioles. Ang II (10-7 M) caused persistent constriction in the Afferent Arterioles pretreated with NG-nitro-L-arginine (10-4 M). Physiological doses of Ang II decresed the lumen diameter of the isolated Afferent Arterioles pretreated with NG-nitro-L-arginine and aspirin DL-lysine. Dup753 (10-6 M), an AT1-receptor antagonist, abolished the vasoconstrictor effects of Ang II. These findings suggest that the isolated rabbit Afferent arteriole has AT1 receptors, and the vasoconstrictor response of Ang II is counteracted by vasodilatory prostaglandins and nitric oxide.
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Role of Nitric Oxide in Desmopressin-Induced Vasodilation of Microperfused Rabbit Afferent Arterioles.
Hypertension research : official journal of the Japanese Society of Hypertension, 1997Co-Authors: Kayo Kiyomoto, Toshiaki Tamaki, Atsufumi Tomohiro, Akira Nishiyama, Shoji Kimura, Yasuharu Aki, Youichi AbeAbstract:We have previously reported that desmopressin (dDAVP) increased the lumen diameter of norepinephrine (NE)-constricted isolated microperfused rabbit Afferent Arterioles. In this study, we examined the role of nitric oxide in dDAVP-induced vasodilation of Afferent Arterioles. We microdissected a superficial Afferent arteriole from the kidney of a New Zealand white rabbit. Each Afferent arteriole was cannulated with a pipette system and microperfused in vitro at 60 mmHg. dDAVP increased the lumen diameter of NE-preconstricted rabbit Afferent Arterioles dose-dependently. dDAVP-induced vasodilation was abolished by pretreatment with NG-nitro-L-arginine (L-NNA, 10(-4)M) (L-NNA + NE, 6.7 +/- 1.1 microns; L-NNA + NE + dDAVP, 7.3 +/- 1.4 microns, n = 8). dDAVP increased the lumen diameter of NE-preconstricted Afferent Arterioles pretreated with L-NNA and L-arginine (10(-2)M) (L-NNA + L-arginine + NE, 6.1 +/- 1.1 microns; L-NNA + L-arginine + NE + dDAVP, 8.7 +/- 0.9 microns*; *p < 0.05, n = 6). Aspirin-DL-lysine (10(-4)M) did not influence dDAVP-induced Afferent arteriolar vasodilation (aspirin + NE, 6.4 +/- 0.8 microns; aspirin + NE + dDAVP, 9.6 +/- 1.3 microns *; *p < 0.05, n = 5). These results suggest that nitric oxide may be responsible for dDAVP-induced Afferent arteriolar vasodilation.
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Vasodilation induced by vasopressin V2 receptor stimulation in Afferent Arterioles
Kidney International, 1996Co-Authors: Toshiaki Tamaki, Kayo Kiyomoto, Atsufumi Tomohiro, Akira Nishiyama, Hong He, Shoji KimuraAbstract:Vasodilation induced by vasopressin V2 receptor stimulation in Afferent Arterioles. We have previously reported that vasopressin (AVP) V2 receptor stimulation increased renal blood flow in dogs anesthetized with pentobarbital. In this study, we examined the direct effects of AVP on Afferent Arterioles to clarify the role played by V2 receptors in regulating Afferent arteriolar tone. We microdissected a superficial Afferent arteriole with glomerulus from the kidney of a New Zealand White rabbit. Each Afferent arteriole was cannulated with a pipette system and microperfused in vitro at 60mm Hg. The effects of vasoactive substances were evaluated by changes in the lumen diameter of Afferent Arterioles. We found that AVP decreased the lumen diameter of microperfused Afferent Arterioles dose-dependently and that a VI antagonist, OPC21268, inhibited the vasoconstrictor action of AVP. However, AVP 10 −8 M increased the lumen diameter of norepinephrine (NE)-constricted Afferent Arterioles pretreated with OPC21268 (OPC+NE, 8.2 ± 0.7 µ m; OPC+NE+AVP, 9.9 ± 0.9 µ m*; * P N = 13). This vasodilatory effect of AVP was abolished by pretreatment with a V2 antagonist, OPC31260. Desmopressin (dDAVP), a V2 agonist, increased the lumen diameter of the NE-constricted Afferent Arterioles (NE, 7.4 ± 0.9 µ m; NE+dDAVP, 10.1 ± 0.7 µ m*; *P
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Vasodilation induced by vasopressin V2 receptor stimulation in Afferent Arterioles
Kidney international, 1996Co-Authors: Toshiaki Tamaki, Kayo Kiyomoto, Atsufumi Tomohiro, Akira Nishiyama, Shoji Kimura, Yasuharu Aki, Youichi AbeAbstract:We have previously reported that vasopressin (AVP) V2 receptor stimulation increased renal blood flow in dogs anesthetized with pentobarbital. In this study, we examined the direct effects of AVP on Afferent Arterioles to clarify the role played by V2 receptors in regulating Afferent arteriolar tone. We microdissected a superficial Afferent arteriole with glomerulus from the kidney of a New Zealand White rabbit. Each Afferent arteriole was cannulated with a pipette system and microperfused in vitro at 60 mm Hg. The effects of vasoactive substances were evaluated by changes in the lumen diameter of Afferent Arterioles. We found that AVP decreased the lumen diameter of microperfused Afferent Arterioles dose-dependently and that a V1 antagonist, OPC21268, inhibited the vasoconstrictor action of AVP. However, AVP 10(-8) M increased the lumen diameter of norepinephrine (NE)-constricted Afferent Arterioles pretreated with OPC21268 (OPC + NE, 8.2 +/- 0.7 microns; OPC + NE + AVP, 9.9 +/- 0.9 microns*; *P < 0.05, N = 13). This vasodilatory effect of AVP was abolished by pretreatment with a V2 antagonist, OPC31260. Desmopressin (dDAVP), a V2 agonist, increased the lumen diameter of the NE-constricted Afferent Arterioles (NE, 7.4 +/- 0.9 microns; NE + dDAVP, 10.1 +/- 0.7 microns*; *P < 0.05, N = 9). These results suggest that AVP V2 receptors are present in rabbit Afferent Arterioles and that V2 receptor stimulation induces vasodilation in rabbit Afferent Arterioles.
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Effects of NG-nitro-L-arginine on isolated rabbit Afferent Arterioles.
Japanese journal of pharmacology, 1993Co-Authors: Toshiaki Tamaki, Shoji Kimura, Yasuharu Aki, Kouichi Hasui, Youichi AbeAbstract:We examined the effects of NG-nitro-L-arginine (L-NNA) on isolated rabbit Afferent Arterioles to confirm that nitric oxide is released at the resistance vessel level in the kidney. We microdissected the superficial Afferent Arterioles from the kidneys of New Zealand White rabbits. Each Afferent arteriole was cannulated with a micropipette system, and the intraluminal pressure was set at 80 mmHg. By our methods, we found that norepinephrine (NE) decreased the lumen diameter of the Afferent Arterioles in a dose-dependent manner, and acetylcholine increased the lumen diameter of NE-constricted Afferent Arterioles. L-NNA (10(-4) M) gradually decreased the lumen diameter of Afferent Arterioles from 21.5 +/- 0.9 to 18.6 +/- 0.9 microns in 20 min, but NG-nitro-D-arginine (10(-4) M) did not affect them (from 21.8 +/- 1.3 to 21.8 +/- 1.5 microns). L-Arginine (10(-2) M) restored the lumen diameter of L-NNA-contracted Afferent Arterioles to the control levels. These findings indicate that the isolated Afferent arteriole has the ability to release or to synthesize and release nitric oxide under basal conditions and that this basal release of nitric oxide plays an important role in the basal tone of the Afferent arteriole.