Document Information

PMID 16135519  (  )
Title Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney.
Abstract Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. We investigated the role of the NAD(P)H oxidase Nox4 in generation of reactive oxygen species (ROS), hypertrophy, and fibronectin expression in a rat model of type 1 diabetes induced by streptozotocin. Phosphorothioated antisense (AS) or sense oligonucleotides for Nox4 were administered for 2 weeks with an osmotic minipump 72 h after streptozotocin treatment. Nox4 protein expression was increased in diabetic kidney cortex compared with non-diabetic controls and was down-regulated in AS-treated animals. AS oligonucleotides inhibited NADPH-dependent ROS generation in renal cortical and glomerular homogenates. ROS generation by intact isolated glomeruli from diabetic animals was increased compared with glomeruli isolated from AS-treated animals. AS treatment reduced whole kidney and glomerular hypertrophy. Moreover, the increased expression of fibronectin protein was markedly reduced in renal cortex including glomeruli of AS-treated diabetic rats. Akt/protein kinase B and ERK1/2, two protein kinases critical for cell growth and hypertrophy, were activated in diabetes, and AS treatment almost abolished their activation. In cultured mesangial cells, high glucose increased NADPH oxidase activity and fibronectin expression, effects that were prevented in cells transfected with AS oligonucleotides. These data establish a role for Nox4 as the major source of ROS in the kidneys during early stages of diabetes and establish that Nox4-derived ROS mediate renal hypertrophy and increased fibronectin expression. Antonio, Texas 78229-3900, USA. gorin@uthscsa.edu

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
7891NOX4NADPH oxidase 4139Nox4-derived | Nox4-transfected | Nox4-treated |
391AKT1v-akt murine thymoma viral oncogene homolog 134pkb alpha | Rac | Akt | PKB | protein kinase b |
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)17Nox2 |
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)17angiotensinogen | angiotensin ii | ang ii | Ang |
14874NOX5NADPH oxidase, EF-hand calcium binding domain 514nadph oxidase |
6877MAPK3mitogen-activated protein kinase 314ERK1 |
6081INSinsulin11insulin |
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))5superoxide dismutase |
19986CYCScytochrome c, somatic4cytochrome c |
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)4p47 protein |
6871MAPK1mitogen-activated protein kinase 13ERK | extracellular signal regulated kinase | ERK2 |
143ACTC1actin, alpha, cardiac muscle 13smooth muscle actin |
25806GSTCDglutathione S-transferase, C-terminal domain containing2glutathione s transferase |
9958RENrenin2renin |
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 12angiotensin converting enzyme |
2577CYBAcytochrome b-245, alpha polypeptide2p22 |
11766TGFB1transforming growth factor, beta 11transforming growth factor beta |
399ALBalbumin1serum albumin |
132ACTBactin, beta1beta actin |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
7891NOX4NADPH oxidase 4Nox47.5investigated the role of the NAD(P)H NAD P H oxidase Nox4 in generation of reactive oxygen species (ROS), ROS hypertrophy and
7891NOX4NADPH oxidase 4Nox47.5Phosphorothioated antisense (AS) AS or sense oligonucleotides for Nox4 were administered for 2 weeks with an osmotic minipump 72
7891NOX4NADPH oxidase 4Nox47.5Nox4 protein expression was increased in diabetic kidney cortex compared with
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5Akt/protein Akt protein kinase B and ERK1/2, ERK1 2 two protein kinases
6877MAPK3mitogen-activated protein kinase 3ERK12.7Akt/protein Akt protein kinase B and ERK1/2, ERK1 2 two protein kinases critical for cell growth and hypertrophy
7891NOX4NADPH oxidase 4Nox47.5These data establish a role for Nox4 as the major source of ROS in the kidneys during
7891NOX4NADPH oxidase 4Nox4-derived0.9the kidneys during early stages of diabetes and establish that Nox4-derived ROS mediate renal hypertrophy and increased fibronectin expression
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3termed Nox proteins correspond to homologues of gp91 (or or Nox2 the catalytic moiety found in phagocytes ( 17 20
7891NOX4NADPH oxidase 4Nox47.5In this family Nox4 which appears to share the same overall structure with gp91
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3appears to share the same overall structure with gp91 /Nox2, Nox2 is abundant in the vascular system kidney cortex and MCs
7891NOX4NADPH oxidase 4Nox47.5However the biological role(s) role s of Nox4 is not well understood at present
7891NOX4NADPH oxidase 4Nox47.5It has been proposed that Nox4 a major source of ROS in the vasculature and the
7891NOX4NADPH oxidase 4Nox4-derived0.9We have reported previously that Nox4-derived ROS mediate angiotensin II (Ang Ang II -induced signaling and
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3have reported previously that Nox4-derived ROS mediate angiotensin II (Ang Ang II -induced signaling and protein synthesis in mesangial cells (
7891NOX4NADPH oxidase 4Nox47.5In this study we determined whether Nox4 mediates ROS generation induced by diabetes in vivo and by
7891NOX4NADPH oxidase 4Nox47.5Antisense oligonucleotides for Nox4 were administered to a rat model of streptozotocin-induced type 1
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5cells in vitro and their effects on oxidative stress Akt/protein Akt protein kinase B (PKB) PKB and extracellular signal-regulated kinases 1
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5effects on oxidative stress Akt/protein Akt protein kinase B (PKB) PKB and extracellular signal-regulated kinases 1 and 2 (ERK1/2) ERK1 2
6877MAPK3mitogen-activated protein kinase 3ERK12.7(PKB) PKB and extracellular signal-regulated kinases 1 and 2 (ERK1/2) ERK1 2 activation renal hypertrophy and fibronectin expression were investigated
7891NOX4NADPH oxidase 4Nox47.5by either phosphorothioated sense or antisense (AS) AS oligonucleotides for Nox4 (90 90 ng/g ng g body weight/day) weight day administered
7891NOX4NADPH oxidase 4Nox47.5oligonucleotides were designed near the ATG start codon of rat Nox4 (5'-AGCTCCTCCAGGACAGCGCC-3') 5'-AGCTCCTCCAGGACAGCGCC-3' ( 27 28
7891NOX4NADPH oxidase 4Nox47.5Transient transfection of antisense and sense oligonucleotides for Nox4 was performed by electroporation or with Lipofectamine as described previously
7891NOX4NADPH oxidase 4Nox47.5Nox4 Expression _amp_#151 TABLE ONE displays the blood glucose levels and
7891NOX4NADPH oxidase 4Nox47.5diabetic rats treated with either AS or the corresponding sense Nox4 had equivalently elevated blood glucose concentration at the end of
7891NOX4NADPH oxidase 4Nox4-treated0.9body weight ratio significantly increased in diabetic rats and sense Nox4-treated diabetic rats compared with non-diabetic control animals
7891NOX4NADPH oxidase 4Nox4-treated0.9In contrast total kidney weight in AS Nox4-treated diabetic rats was significantly reduced compared with that observed for
7891NOX4NADPH oxidase 4Nox4-treated0.9reduced compared with that observed for the diabetic or sense Nox4-treated diabetic groups ( TABLE ONE
7891NOX4NADPH oxidase 4Nox47.5In this study we demonstrate that Nox4 is a major source of ROS overproduction in diabetes and
7891NOX4NADPH oxidase 4Nox4-derived0.9a major source of ROS overproduction in diabetes and that Nox4-derived ROS mediate Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5ROS overproduction in diabetes and that Nox4-derived ROS mediate Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation kidney hypertrophy and fibronectin
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5overproduction in diabetes and that Nox4-derived ROS mediate Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation kidney hypertrophy and fibronectin expression
6877MAPK3mitogen-activated protein kinase 3ERK12.7and that Nox4-derived ROS mediate Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation kidney hypertrophy and fibronectin expression
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p471.4the catalytic subunit gp91 together with the regulatory subunits p22 p47 and p67 and the small GTPase Rac ( 17 20
391AKT1v-akt murine thymoma viral oncogene homolog 1Rac1.5regulatory subunits p22 p47 and p67 and the small GTPase Rac ( 17 20 40
2577CYBAcytochrome b-245, alpha polypeptidep220.1of the catalytic subunit gp91 together with the regulatory subunits p22 p47 and p67 and the small GTPase Rac ( 17
7891NOX4NADPH oxidase 4Nox47.5The isoform Nox4 was cloned from the kidney and found to be highly
7891NOX4NADPH oxidase 4Nox47.5Nox4 is nearly identical in size and structure to gp91 (also
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3in size and structure to gp91 (also also known as Nox2
7891NOX4NADPH oxidase 4Nox47.5However the requirement for Nox4 activity of other components of the gp91 /Nox2 Nox2 complex
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3for Nox4 activity of other components of the gp91 /Nox2 Nox2 complex is not known
7891NOX4NADPH oxidase 4Nox47.5Nox4 is a 578-amino acid protein that exhibits 39% identity to
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3578-amino acid protein that exhibits 39% identity to gp91 /Nox2 Nox2 with special conservation in the membrane-spanning regions and binding sites
7891NOX4NADPH oxidase 4Nox47.5We show increased expression of Nox4 protein in the kidney of STZ-induced diabetic rats that is
7891NOX4NADPH oxidase 4Nox47.5Immunostaining analysis reveals that diabetes up-regulates Nox4 protein levels in a pattern consistent with mesangial cell distribution
7891NOX4NADPH oxidase 4Nox47.5The administration of AS Nox4 markedly inhibited diabetes-induced NADPH oxidase activity concomitantly with the down-regulation
7891NOX4NADPH oxidase 4Nox47.5inhibited diabetes-induced NADPH oxidase activity concomitantly with the down-regulation of Nox4 protein expression
7891NOX4NADPH oxidase 4Nox47.5The increases in Nox4 protein expression and ROS generation were prevented by insulin treatment
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3Interestingly gp91 /Nox2 Nox2 was also up-regulated in the diabetic kidney
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.341 -43 showing that diabetes enhanced expression of gp91 /Nox2 Nox2 in the kidney and vasculature
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3However no attenuation of gp91 /Nox2 Nox2 expression was seen in AS Nox4-treated rats indicating that the
7891NOX4NADPH oxidase 4Nox4-treated0.9attenuation of gp91 /Nox2 Nox2 expression was seen in AS Nox4-treated rats indicating that the decrease in ROS generation is related
7891NOX4NADPH oxidase 4Nox47.5the decrease in ROS generation is related to inhibition of Nox4
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3lack of correlation between ROS generation and increased gp91 /Nox2 Nox2 expression in the AS Nox4-treated animals is somewhat surprising
7891NOX4NADPH oxidase 4Nox4-treated0.9generation and increased gp91 /Nox2 Nox2 expression in the AS Nox4-treated animals is somewhat surprising
7891NOX4NADPH oxidase 4Nox47.5However unlike the requirement for Nox4 activation activation of gp91 /Nox2 Nox2 is dependent on a
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3unlike the requirement for Nox4 activation activation of gp91 /Nox2 Nox2 is dependent on a number of cytosolic and membrane subunits
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3there is emerging evidence that in contrast to gp91 /Nox2, Nox2 Nox4 functions independently of the presence of the cytosolic subunits
7891NOX4NADPH oxidase 4Nox47.5is emerging evidence that in contrast to gp91 /Nox2, Nox2 Nox4 functions independently of the presence of the cytosolic subunits (
7891NOX4NADPH oxidase 4Nox47.5Therefore it is tempting to speculate that Nox4 activity depends primarily on the expression of the catalytic unit
7891NOX4NADPH oxidase 4Nox47.5explanation will await a better understanding of the mechanism of Nox4 activation and its precise subunit requirement
7891NOX4NADPH oxidase 4Nox47.5In addition the function of Nox4 as source of ROS in diabetes is supported by the
7891NOX4NADPH oxidase 4Nox47.5the in vitro observation that transfection of MCs with AS Nox4 markedly reduced high glucose-induced NADPH oxidase activation
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 treatment on Nox4 and gp91 /Nox2 Nox2 protein expression in
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 treatment on Nox4 and gp91 /Nox2 Nox2 protein expression in the diabetic kidney
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3Effects of AS Nox4 treatment on Nox4 and gp91 /Nox2 Nox2 protein expression in the diabetic kidney
7891NOX4NADPH oxidase 4Nox47.5A expression of Nox4 and gp91 /Nox2 Nox2 protein was determined by direct immunoblotting
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3A expression of Nox4 and gp91 /Nox2 Nox2 protein was determined by direct immunoblotting of homogenized kidney cortex
7891NOX4NADPH oxidase 4Nox47.5bottom panel represents the ratio of the intensity of the Nox4 ( alpha-smooth muscle actin ( b and merge ( c
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 treatment on diabetes-induced ROS generation
7891NOX4NADPH oxidase 4Nox47.5in glomerular homogenates from control ( diabetes ( diabetes sense Nox4 ( and diabetes AS Nox4 ( groups
7891NOX4NADPH oxidase 4Nox47.5( diabetes ( diabetes sense Nox4 ( and diabetes AS Nox4 ( groups
7891NOX4NADPH oxidase 4Nox47.5Effects of insulin treatment on diabetes-induced Nox4 expression and ROS generation in the kidney
7891NOX4NADPH oxidase 4Nox47.5A expression of Nox4 protein was determined by direct immunoblotting of homogenized kidney cortex
7891NOX4NADPH oxidase 4Nox47.5B Nox4 expression and localization were detected by immunoperoxidase staining of kidney
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 treatment on renal hypertrophy
7891NOX4NADPH oxidase 4Nox47.5eosin from control ( a diabetes ( b diabetes sense Nox4 ( c and diabetes AS Nox4 ( d groups
7891NOX4NADPH oxidase 4Nox47.5( b diabetes sense Nox4 ( c and diabetes AS Nox4 ( d groups
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 treatment on diabetes-induced fibronectin accumulation
7891NOX4NADPH oxidase 4Nox47.5sections from control ( a diabetes ( b diabetes sense Nox4 ( c and diabetes AS Nox4 ( d groups
7891NOX4NADPH oxidase 4Nox47.5( b diabetes sense Nox4 ( c and diabetes AS Nox4 ( d groups
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 treatment on Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5Effects of AS Nox4 treatment on Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5Effects of AS Nox4 treatment on Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation
6877MAPK3mitogen-activated protein kinase 3ERK12.7of AS Nox4 treatment on Akt/PKB Akt PKB and ERK1/2 ERK1 2 activation
6877MAPK3mitogen-activated protein kinase 3ERK12.7ERK1/2 ERK1 2 and Akt/PKB Akt PKB phosphorylation was assessed in cortical
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5ERK1/2 ERK1 2 and Akt/PKB Akt PKB phosphorylation was assessed in cortical homogenates using anti-phospho-specific ERK1/2
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5ERK1/2 ERK1 2 and Akt/PKB Akt PKB phosphorylation was assessed in cortical homogenates using anti-phospho-specific ERK1/2 ERK1
6877MAPK3mitogen-activated protein kinase 3ERK12.7PKB phosphorylation was assessed in cortical homogenates using anti-phospho-specific ERK1/2 ERK1 2 and Akt/PKB Akt PKB antibodies
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5in cortical homogenates using anti-phospho-specific ERK1/2 ERK1 2 and Akt/PKB Akt PKB antibodies
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5cortical homogenates using anti-phospho-specific ERK1/2 ERK1 2 and Akt/PKB Akt PKB antibodies
7891NOX4NADPH oxidase 4Nox47.5Effects of AS Nox4 on high glucose-induced ROS generation and fibronectin expression in MCs
7891NOX4NADPH oxidase 4Nox47.5not ( Con or were transfected by electroporation with sense Nox4 (1 1 micro M or AS Nox4 (1 1 micro
7891NOX4NADPH oxidase 4Nox47.5electroporation with sense Nox4 (1 1 micro M or AS Nox4 (1 1 micro M and Nox4 protein expression was determined
7891NOX4NADPH oxidase 4Nox47.5micro M or AS Nox4 (1 1 micro M and Nox4 protein expression was determined by direct immunoblotting with mouse polyclonal
7891NOX4NADPH oxidase 4Nox47.5protein expression was determined by direct immunoblotting with mouse polyclonal Nox4 antibodies
7891NOX4NADPH oxidase 4Nox47.5superoxide generation measured in homogenates of MCs transfected by sense Nox4 or AS Nox4 and exposed to NG (5 5 m
7891NOX4NADPH oxidase 4Nox47.5in homogenates of MCs transfected by sense Nox4 or AS Nox4 and exposed to NG (5 5 m M D -glucose
7891NOX4NADPH oxidase 4Nox47.5-glucose for 24 h with or without AS and sense Nox4
7891NOX4NADPH oxidase 4Nox47.5D MCs were transfected with sense Nox4 or AS Nox4 by using Lipofectamine and exposed to NG
7891NOX4NADPH oxidase 4Nox47.5D MCs were transfected with sense Nox4 or AS Nox4 by using Lipofectamine and exposed to NG HG or 5
7891NOX4NADPH oxidase 4Nox47.5in Tris-buffered saline and then incubated with a mouse polyclonal Nox4 antibody directed against recombinant glutathione S -transferase-mouse Nox4-(299-515) Nox4- 299-515
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5Thr /Tyr Tyr antibody or a rabbit polyclonal anti-Akt1/PKB anti-Akt1 PKB alpha ( Cell Signaling Technology Inc.
7891NOX4NADPH oxidase 4Nox47.5of cellular fibronectin was assessed by immunoperoxidase histochemistry using polyclonal Nox4 antibodies or mouse monoclonal antibodies specific for the alternatively spliced
7891NOX4NADPH oxidase 4Nox47.5the kidney and to assess the effect of diabetes on Nox4 expression we examined the protein levels of Nox4 in renal
7891NOX4NADPH oxidase 4Nox47.5diabetes on Nox4 expression we examined the protein levels of Nox4 in renal cortex from the different groups
7891NOX4NADPH oxidase 4Nox47.5Western blot analysis using a mouse polyclonal Nox4 antibody directed against recombinant glutathione S -transferase-mouse Nox4-(299-515) Nox4- 299-515
7891NOX4NADPH oxidase 4Nox47.5Nox4- 299-515 showed that a predominant 70-kDa band corresponding to Nox4 was increased in diabetic kidney cortex compared with that in
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 but not sense Nox4 administration reversed diabetes-induced Nox4 protein expression
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 but not sense Nox4 administration reversed diabetes-induced Nox4 protein expression and significantly reduced Nox4
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 but not sense Nox4 administration reversed diabetes-induced Nox4 protein expression and significantly reduced Nox4 levels in kidney cortex
7891NOX4NADPH oxidase 4Nox47.5Nox4 administration reversed diabetes-induced Nox4 protein expression and significantly reduced Nox4 levels in kidney cortex from diabetic animals ( Fig 1
7891NOX4NADPH oxidase 4Nox47.5confirm the specificity of action of the AS treatment toward Nox4 we also examined the protein expression of another Nox isoform
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3examined the protein expression of another Nox isoform gp91 /Nox2 Nox2
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3The levels of gp91 /Nox2 Nox2 were also increased in diabetic animals
7891NOX4NADPH oxidase 4Nox47.5More importantly administration of AS Nox4 had no effect on gp91 /Nox2 Nox2 expression ( Fig
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3administration of AS Nox4 had no effect on gp91 /Nox2 Nox2 expression ( Fig 1 A
7891NOX4NADPH oxidase 4Nox47.5Immunoperoxidase staining showed that Nox4 protein expression is significantly increased in diabetic glomeruli
7891NOX4NADPH oxidase 4Nox47.5AS but not sense Nox4 administration markedly reduced diabetes-induced Nox4 protein expression ( Fig 1
7891NOX4NADPH oxidase 4Nox47.5AS but not sense Nox4 administration markedly reduced diabetes-induced Nox4 protein expression ( Fig 1 B
7891NOX4NADPH oxidase 4Nox47.5Double immunofluorescence staining revealed the colocalization of Nox4 ( green and alpha-smooth muscle actin ( red in the
7891NOX4NADPH oxidase 4Nox47.5These observations demonstrate that Nox4 expression is consistent with mesangial distribution
7891NOX4NADPH oxidase 4Nox47.5These data indicate that mesangial expression of Nox4 is increased in diabetes and that subcutaneous administration of AS
7891NOX4NADPH oxidase 4Nox47.5that subcutaneous administration of AS oligonucleotides effectively and specifically inhibits Nox4 NAD(P)H NAD P H oxidase expression
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 but not sense Nox4 treatment suppressed diabetes-induced NADPH oxidase activation
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 but not sense Nox4 treatment suppressed diabetes-induced NADPH oxidase activation in cortical and glomerular
7891NOX4NADPH oxidase 4Nox47.5the inhibitions of NADPH-dependent ROS generation and the decrease in Nox4 expression following AS Nox4 administration in the diabetic rats suggest
7891NOX4NADPH oxidase 4Nox47.5ROS generation and the decrease in Nox4 expression following AS Nox4 administration in the diabetic rats suggest that Nox4 is the
7891NOX4NADPH oxidase 4Nox47.5following AS Nox4 administration in the diabetic rats suggest that Nox4 is the enzyme responsible for the increase in NADPH oxidase
7891NOX4NADPH oxidase 4Nox47.5To further confirm the inhibitory effect of AS Nox4 on diabetes-induced oxidative stress in glomeruli superoxide generation was evaluated
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 treatment significantly inhibited the increase in superoxide anion production in
7891NOX4NADPH oxidase 4Nox47.5Conversely superoxide release was not affected by sense Nox4 treatment ( Fig 2 C
7891NOX4NADPH oxidase 4Nox47.5Insulin Treatment _amp_#151 To determine whether the increased expression of Nox4 and ROS generation were because of the diabetic state and
7891NOX4NADPH oxidase 4Nox47.5and immunochemical analysis showed that the increased protein levels of Nox4 in diabetic rat kidneys were completely prevented in the rats
7891NOX4NADPH oxidase 4Nox47.5Treatment with AS Nox4 but not sense Nox4 resulted in a significant decrease in
7891NOX4NADPH oxidase 4Nox47.5Treatment with AS Nox4 but not sense Nox4 resulted in a significant decrease in kidney weight ( TABLE
7891NOX4NADPH oxidase 4Nox47.5These data suggest that Nox4 is involved in renal hypertrophy
7891NOX4NADPH oxidase 4Nox4-treated0.9in histological sections of kidneys removed from control diabetic AS Nox4-treated and sense Nox4-treated rats
7891NOX4NADPH oxidase 4Nox4-treated0.9of kidneys removed from control diabetic AS Nox4-treated and sense Nox4-treated rats
7891NOX4NADPH oxidase 4Nox47.5AS Nox4 treatment resulted in a decrease in glomerular size
7891NOX4NADPH oxidase 4Nox4-treated0.9In contrast glomeruli from sense Nox4-treated animals are not different from glomeruli of diabetic animals
7891NOX4NADPH oxidase 4Nox47.5Collectively these results demonstrate that AS Nox4 treatment reduces whole kidney and glomerular hypertrophy in diabetic animals
7891NOX4NADPH oxidase 4Nox47.5whole kidney and glomerular hypertrophy in diabetic animals suggesting that Nox4 is positioned distal to hyperglycemia in the pathway that leads
7891NOX4NADPH oxidase 4Nox47.5Fibronectin Expression _amp_#151 The effect of AS Nox4 administration on the accumulation of the extracellular matrix protein fibronectin
7891NOX4NADPH oxidase 4Nox47.5renal cortex and glomeruli of diabetic rats treated with AS Nox4 ( Fig 5 A and B
7891NOX4NADPH oxidase 4Nox47.5Sense Nox4 treatment had no effect on diabetes-induced fibronectin expression
7891NOX4NADPH oxidase 4Nox47.5was increased in the diabetic group and treatment with AS Nox4 decreased the increased expression of fibronectin induced by diabetes
7891NOX4NADPH oxidase 4Nox47.5Sense Nox4 treatment did not alter the enhanced immunoreactivity of fibronectin observed
7891NOX4NADPH oxidase 4Nox47.5Quantitative analysis revealed a significant inhibitory effect of AS Nox4 on glomerular expression of fibronectin induced by diabetes as compared
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5Akt/PKB Akt PKB and ERK1/2 ERK1 2 Phosphorylation _amp_#151 The serine-threonine kinase
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5Akt/PKB Akt PKB and ERK1/2 ERK1 2 Phosphorylation _amp_#151 The serine-threonine kinase Akt/PKB
6877MAPK3mitogen-activated protein kinase 3ERK12.7Akt/PKB Akt PKB and ERK1/2 ERK1 2 Phosphorylation _amp_#151 The serine-threonine kinase Akt/PKB Akt PKB and
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5and ERK1/2 ERK1 2 Phosphorylation _amp_#151 The serine-threonine kinase Akt/PKB Akt PKB and the mitogen-activated protein kinase family members ERK1 and
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5ERK1/2 ERK1 2 Phosphorylation _amp_#151 The serine-threonine kinase Akt/PKB Akt PKB and the mitogen-activated protein kinase family members ERK1 and -2
6877MAPK3mitogen-activated protein kinase 3ERK12.7Akt/PKB Akt PKB and the mitogen-activated protein kinase family members ERK1 and -2 are activated by phosphorylation
6871MAPK1mitogen-activated protein kinase 1ERK21.7Akt/PKB Akt PKB and the mitogen-activated protein kinase family members ERK1 and -2 are activated by phosphorylation
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5of these kinases during early DN the phosphorylation of Akt/PKB Akt PKB and ERK1/2 ERK1 2 was examined using phospho-specific antibodies
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5these kinases during early DN the phosphorylation of Akt/PKB Akt PKB and ERK1/2 ERK1 2 was examined using phospho-specific antibodies
6877MAPK3mitogen-activated protein kinase 3ERK12.7early DN the phosphorylation of Akt/PKB Akt PKB and ERK1/2 ERK1 2 was examined using phospho-specific antibodies
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5As illustrated in Fig 6 phosphorylation of both Akt/PKB Akt PKB and ERK1/2 ERK1 2 was markedly increased in the
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5As illustrated in Fig 6 phosphorylation of both Akt/PKB Akt PKB and ERK1/2 ERK1 2 was markedly increased in the diabetic
6877MAPK3mitogen-activated protein kinase 3ERK12.7Fig 6 phosphorylation of both Akt/PKB Akt PKB and ERK1/2 ERK1 2 was markedly increased in the diabetic kidney cortex and
7891NOX4NADPH oxidase 4Nox47.5diabetic kidney cortex and treatment of diabetic animals with AS Nox4 but not sense Nox4 almost abolished this effect
7891NOX4NADPH oxidase 4Nox47.5treatment of diabetic animals with AS Nox4 but not sense Nox4 almost abolished this effect
7891NOX4NADPH oxidase 4Nox47.5These findings demonstrate that Nox4 is required for diabetes-induced Akt/PKB Akt PKB and ERK1/2 ERK1
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5These findings demonstrate that Nox4 is required for diabetes-induced Akt/PKB Akt PKB and ERK1/2 ERK1 2 phosphorylation and that the two
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5findings demonstrate that Nox4 is required for diabetes-induced Akt/PKB Akt PKB and ERK1/2 ERK1 2 phosphorylation and that the two kinases
6877MAPK3mitogen-activated protein kinase 3ERK12.7Nox4 is required for diabetes-induced Akt/PKB Akt PKB and ERK1/2 ERK1 2 phosphorylation and that the two kinases are positioned downstream
7891NOX4NADPH oxidase 4Nox47.5phosphorylation and that the two kinases are positioned downstream of Nox4 in the signaling pathway(s) pathway s activated in diabetes
7891NOX4NADPH oxidase 4Nox47.5Mesangial Cells _amp_#151 We also assessed the effects of AS Nox4 on ROS production and fibronectin accumulation in cultured rat MCs
7891NOX4NADPH oxidase 4Nox47.5oligonucleotides in MCs was confirmed by the observation that AS Nox4 but not sense Nox4 significantly decreased Nox4 protein expression (
7891NOX4NADPH oxidase 4Nox47.5confirmed by the observation that AS Nox4 but not sense Nox4 significantly decreased Nox4 protein expression ( Fig 7 A
7891NOX4NADPH oxidase 4Nox47.5observation that AS Nox4 but not sense Nox4 significantly decreased Nox4 protein expression ( Fig 7 A
7891NOX4NADPH oxidase 4Nox4-transfected0.9AS Nox4- or sense Nox4-transfected MCs were incubated for 24 h in serum-free medium containing
7891NOX4NADPH oxidase 4Nox47.5Transient transfection of MCs with AS Nox4 (1 1 micro M but not sense Nox4 (1 1
7891NOX4NADPH oxidase 4Nox47.5with AS Nox4 (1 1 micro M but not sense Nox4 (1 1 micro M markedly decreased the activation of NADPH
7891NOX4NADPH oxidase 4Nox47.5ROS production was significantly blocked in MCs transfected with AS Nox4
7891NOX4NADPH oxidase 4Nox47.5fluorescence was not affected by transfection of MCs with sense Nox4
7891NOX4NADPH oxidase 4Nox47.5Similar to ROS generation transfection of MCs with AS Nox4 significantly decreased HG-mediated increase in fibronectin expression ( Fig 7
7891NOX4NADPH oxidase 4Nox47.5In contrast sense Nox4 did not alter the increase in fibronectin accumulation in MCs
7891NOX4NADPH oxidase 4Nox47.5These findings demonstrate that Nox4 NAD(P)H NAD P H oxidase is involved in HG-stimulated extracellular
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p471.4high glucose-induced ROS generation also occurs through activation of a p47 -containing NAD(P)H NAD P H oxidase in cultured cells (
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox22.3diabetes characterized by an up-regulation of p22 and gp91 /Nox2 Nox2 ( 43
2577CYBAcytochrome b-245, alpha polypeptidep220.0model of type 2 diabetes characterized by an up-regulation of p22 and gp91 /Nox2 Nox2 ( 43
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3( 57 recently reported that Ang II-induced ROS generation via NAD(P)H NAD P H oxidase triggered
7891NOX4NADPH oxidase 4Nox4-derived0.9Our work not only demonstrated that Nox4-derived ROS contribute to oxidative stress during the initial stages of
7891NOX4NADPH oxidase 4Nox47.5Inhibition of Nox4 oxidase by administration of AS Nox4 reduced whole kidney hypertrophy
7891NOX4NADPH oxidase 4Nox47.5Inhibition of Nox4 oxidase by administration of AS Nox4 reduced whole kidney hypertrophy and glomerular hypertrophy as well as
7891NOX4NADPH oxidase 4Nox47.5Furthermore transfection of cultured MCs with AS Nox4 significantly reduced high glucose-induced accumulation of fibronectin
7891NOX4NADPH oxidase 4Nox47.5They may exert a direct effect on Nox4 to stimulate hypertrophy and fibronectin expression or indirectly via the
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3or indirectly via the release of other mediators such as Ang II and/or and or transforming growth factor-beta.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3We have shown previously that Ang II induces protein synthesis and hypertrophy via Nox4 in MCs
7891NOX4NADPH oxidase 4Nox47.5previously that Ang II induces protein synthesis and hypertrophy via Nox4 in MCs ( 27 28
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p471.4that ROS generation and NAD(P)H NAD P H oxidase subunit p47 protein expression were increased in glomeruli of rats with type
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3that were inhibited by treatment with angiotensin-converting enzyme inhibitor or Ang II type 1 (AT AT 1 receptor blocker ( 13
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3High glucose concentration enhances Ang II generation via up-regulation of angiotensinogen angiotensin-converting enzyme or renin
7891NOX4NADPH oxidase 4Nox47.5We further dissected the involvement of Nox4 by identifying the downstream targets of the oxidase in the
6877MAPK3mitogen-activated protein kinase 3ERK12.7There is evidence that ERK1/2 ERK1 2 mediates hypertrophy and extracellular matrix accumulation both in animal
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5In vitro studies suggested that activation of the Akt/PKB Akt PKB pathway is involved in renal cell hypertrophy or matrix
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5In vitro studies suggested that activation of the Akt/PKB Akt PKB pathway is involved in renal cell hypertrophy or matrix accumulation
6877MAPK3mitogen-activated protein kinase 3ERK12.7We now demonstrate that both ERK1/2 ERK1 2 and Akt/PKB Akt PKB are activated in vivo and
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5We now demonstrate that both ERK1/2 ERK1 2 and Akt/PKB Akt PKB are activated in vivo and that inhibition of Nox4
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5now demonstrate that both ERK1/2 ERK1 2 and Akt/PKB Akt PKB are activated in vivo and that inhibition of Nox4 function
7891NOX4NADPH oxidase 4Nox47.5Akt PKB are activated in vivo and that inhibition of Nox4 function with AS Nox4 nearly abrogates diabetes-induced activation of ERK1/2
7891NOX4NADPH oxidase 4Nox47.5in vivo and that inhibition of Nox4 function with AS Nox4 nearly abrogates diabetes-induced activation of ERK1/2 ERK1 2 and Akt/PKB,
6877MAPK3mitogen-activated protein kinase 3ERK12.7function with AS Nox4 nearly abrogates diabetes-induced activation of ERK1/2 ERK1 2 and Akt/PKB, Akt PKB suggesting that Nox4 functions as
391AKT1v-akt murine thymoma viral oncogene homolog 1Akt1.5nearly abrogates diabetes-induced activation of ERK1/2 ERK1 2 and Akt/PKB, Akt PKB suggesting that Nox4 functions as an upstream activator of
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.5abrogates diabetes-induced activation of ERK1/2 ERK1 2 and Akt/PKB, Akt PKB suggesting that Nox4 functions as an upstream activator of the
7891NOX4NADPH oxidase 4Nox47.5of ERK1/2 ERK1 2 and Akt/PKB, Akt PKB suggesting that Nox4 functions as an upstream activator of the two kinases not
7891NOX4NADPH oxidase 4Nox47.5It is tempting to speculate that Nox4 is a pivotal signal transducer commonly shared by both hypertrophic
7891NOX4NADPH oxidase 4Nox47.5establishes that activation of the NAD(P)H NAD P H oxidase Nox4 plays a critical role in diabetes-induced oxidative stress kidney hypertrophy
7891NOX4NADPH oxidase 4Nox47.5abbreviations used are DN diabetic nephropathy ROS reactive oxygen species Nox4 NAD(P)H NAD P H oxidase 4 MC mesangial cell AS
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)Ang0.3oligonucleotides NG normal glucose HG high glucose DCF 2' 7'-dichlorodihydrofluorescein Ang II angiotensin II ERK extracellular signal-regulated kinase PKB protein kinase
6871MAPK1mitogen-activated protein kinase 1ERK1.7HG high glucose DCF 2' 7'-dichlorodihydrofluorescein Ang II angiotensin II ERK extracellular signal-regulated kinase PKB protein kinase B STZ streptozotocin RLU
391AKT1v-akt murine thymoma viral oncogene homolog 1PKB1.52' 7'-dichlorodihydrofluorescein Ang II angiotensin II ERK extracellular signal-regulated kinase PKB protein kinase B STZ streptozotocin RLU relative light units PBS
391AKT1v-akt murine thymoma viral oncogene homolog 1protein kinase b1.0akt/protein kinase b and erk1/2 two protein kinases critical for cell growth and hypertrophy were activated in diabetes and as treatment almost abolished their activation.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in cultured mesangial cells high glucose increased nadph oxidase activity and fibronectin expression effects that were prevented in cells transfected with as oligonucleotides.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0we have reported previously that nox4 derived ros mediate angiotensin ii ang ii induced signaling and protein synthesis in mesangial cells 27 28 suggesting its potential involvement in kidney hypertrophy under pathologic conditions.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensin ii1.0we have reported previously that nox4 derived ros mediate angiotensin ii ang ii induced signaling and protein synthesis in mesangial cells 27 28 suggesting its potential involvement in kidney hypertrophy under pathologic conditions.
391AKT1v-akt murine thymoma viral oncogene homolog 1protein kinase b1.0antisense oligonucleotides for nox4 were administered to a rat model of streptozotocin induced type 1 diabetes and to cultured cells in vitro and their effects on oxidative stress akt/protein kinase b pkb and extracellular signal regulated kinases 1 and 2 erk1/2 activation renal hypertrophy and fibronectin expression were investigated.
6081INSinsulininsulin1.0three additional groups of control diabetic and diabetic rats treated with insulin were also studied.
6081INSinsulininsulin1.0twenty four h after stz injection diabetic rats were treated daily with 4 6 units of nph insulin supplemented with regular insulin novo nordisk pharmaceuticals inc. princeton nj subcutaneously.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0nadph oxidase assay
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0nadph oxidase activity was measured by the lucigenin enhanced chemiluminescence method.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0measurement of superoxide anion released by isolated glomeruli was performed by detection of superoxide dismutase inhibitable ferricytochrome c reduction 27 31 .
19986CYCScytochrome c, somaticcytochrome c1.0isolated glomeruli were incubated in hanks' balanced salt solution without phenol red containing 80 micro m cytochrome c with or without superoxide dismutase 50 microg/ml for 6 h at 37 degreec.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0isolated glomeruli were incubated in hanks' balanced salt solution without phenol red containing 80 micro m cytochrome c with or without superoxide dismutase 50 microg/ml for 6 h at 37 degreec.
19986CYCScytochrome c, somaticcytochrome c1.0the optical density of the supernatant was measured by spectrophotometry at 550 nm and converted to nmol of cytochrome c reduced using the extinction coefficient delta e 550 = 21.0 x 10 m cm .
19986CYCScytochrome c, somaticcytochrome c1.0the reduction of cytochrome c that was inhibitable by pretreatment with superoxide dismutase represents superoxide release.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0the reduction of cytochrome c that was inhibitable by pretreatment with superoxide dismutase represents superoxide release.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the administration of as nox4 markedly inhibited diabetes induced nadph oxidase activity concomitantly with the down regulation of nox4 protein expression.
6081INSinsulininsulin1.0the increases in nox4 protein expression and ros generation were prevented by insulin treatment suggesting that these changes were caused by the diabetic state and were not a direct toxic effect of stz.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in addition the function of nox4 as source of ros in diabetes is supported by the in vitro observation that transfection of mcs with as nox4 markedly reduced high glucose induced nadph oxidase activation.
143ACTC1actin, alpha, cardiac muscle 1smooth muscle actin1.0each histogram in the bottom panel represents the ratio of the intensity of the nox4 alpha smooth muscle actin b and merge c in cortical sections from diabetic rats.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0a nadph oxidase activity in cortical homogenates.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0b nadph oxidase activity in glomerular homogenates from control diabetes diabetes + sense nox4 and diabetes + as nox4 groups.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0c superoxide anion release by isolated glomeruli was assessed by superoxide dismutase inhibitable ferricytochrome c reduction as described under "experimental procedures."
6081INSinsulininsulin1.0effects of insulin treatment on diabetes induced nox4 expression and ros generation in the kidney.
6081INSinsulininsulin1.0b nox4 expression and localization were detected by immunoperoxidase staining of kidney sections from control a diabetes b and diabetes + insulin c .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0c nadph oxidase activity in cortical homogenates.
25806GSTCDglutathione S-transferase, C-terminal domain containingglutathione s transferase1.0the membranes were blocked with 5% low fat milk in tris buffered saline and then incubated with a mouse polyclonal nox4 antibody directed against recombinant glutathione s transferase mouse nox4 299 515 dilution 1:1 000 a rabbit polyclonal anti gp91 upstate %20biotechnology"> upstate biotechnology inc.
132ACTBactin, betabeta actin1.0 1:1 000 a rabbit polyclonal anti fibronectin antibody sigma 1:2 500 or a mouse monoclonal anti beta actin 1:4 000 and a rabbit anti phospho akt ser antibody a rabbit anti phospho erk1/2 thr /tyr antibody or a rabbit polyclonal anti akt1/pkb alpha cell signaling technology inc.
391AKT1v-akt murine thymoma viral oncogene homolog 1pkb alpha1.0onectin antibody sigma 1:2 500 or a mouse monoclonal anti beta actin 1:4 000 and a rabbit anti phospho akt ser antibody a rabbit anti phospho erk1/2 thr /tyr antibody or a rabbit polyclonal anti akt1/pkb alpha cell signaling technology inc.
143ACTC1actin, alpha, cardiac muscle 1smooth muscle actin1.0sections were mounted with crystal mount dako and allowed to dry before viewing with fluorescence microscopy. alpha smooth muscle actin was used as a marker for mcs within the glomerulus.
25806GSTCDglutathione S-transferase, C-terminal domain containingglutathione s transferase1.0western blot analysis using a mouse polyclonal nox4 antibody directed against recombinant glutathione s transferase mouse nox4 299 515 showed that a predominant 70 kda band corresponding to nox4 was increased in diabetic kidney cortex compared with that in control non diabetic rats.
143ACTC1actin, alpha, cardiac muscle 1smooth muscle actin1.0double immunofluorescence staining revealed the colocalization of nox4 green and alpha smooth muscle actin red in the mesangial area of diabetic glomeruli fig 1 c .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0as nox4 but not sense nox4 treatment suppressed diabetes induced nadph oxidase activation in cortical and glomerular homogenates fig 2 a and b .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0preincubation of homogenates with diphenyleneiodonium an inhibitor of flavin containing oxidases completely blocked nadph oxidase activity.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0in addition superoxide dismutase 50 microg/ml also inhibited the photoemission thereby confirming identity of the product as superoxide data not shown .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0inhibitions of nadph dependent ros generation and the decrease in nox4 expression following as nox4 administration in the diabetic rats suggest that nox4 is the enzyme responsible for the increase in nadph oxidase activity in diabetes.
19986CYCScytochrome c, somaticcytochrome c1.0to further confirm the inhibitory effect of as nox4 on diabetes induced oxidative stress in glomeruli superoxide generation was evaluated ex vivo in isolated glomeruli incubated in the presence of cytochrome c .
6081INSinsulininsulin1.0effects of insulin treatment _amp_#151;to determine whether the increased expression of nox4 and ros generation were because of the diabetic state and not because of a toxic effect of stz diabetic rats were treated wit
6081INSinsulininsulin1.0reatment _amp_#151;to determine whether the increased expression of nox4 and ros generation were because of the diabetic state and not because of a toxic effect of stz diabetic rats were treated with insulin.
6081INSinsulininsulin1.0tight glycemic control was achieved in the diabetic rats treated with insulin mean plasma glucose concentrations on the last day were 102.6 mg/dl _amp_#177; 3.9 in control rats 433.5 mg/dl _amp_#177; 25.8 in diabetic rats and 103.7 mg/dl _amp_#177; 32.9 in diabetic rats treate
6081INSinsulininsulin1.0lasma glucose concentrations on the last day were 102.6 mg/dl _amp_#177; 3.9 in control rats 433.5 mg/dl _amp_#177; 25.8 in diabetic rats and 103.7 mg/dl _amp_#177; 32.9 in diabetic rats treated with insulin .
6081INSinsulininsulin1.0western blot and immunochemical analysis showed that the increased protein levels of nox4 in diabetic rat kidneys were completely prevented in the rats treated with insulin fig 3 a and b .
6081INSinsulininsulin1.0in addition the increase in nadph oxidase activity in cortical homogenates from diabetic animals was also prevented in the diabetic rats treated with insulin fig 3 c .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in addition the increase in nadph oxidase activity in cortical homogenates from diabetic animals was also prevented in the diabetic rats treated with insulin fig 3 c .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0sense nox4 transfected mcs were incubated for 24 h in serum free medium containing either normal glucose concentration ng 5 m m d glucose hg 25 m m d glucose or 5 m m d glucose + 20 m m l glucose and nadph oxidase activity was measured in crude homogenates using lucigenin enhanced chemiluminescence.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0transient transfection of mcs with as nox4 1 micro m but not sense nox4 1 micro m markedly decreased the activation of nadph oxidase by hg.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0 57 recently reported that ang ii induced ros generation via nad p h oxidase triggered mitochondrial ros release in cardiac myocytes.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0they may exert a direct effect on nox4 to stimulate hypertrophy and fibronectin expression or indirectly via the release of other mediators such as ang ii and/or transforming growth factor beta.
11766TGFB1transforming growth factor, beta 1transforming growth factor beta1.0they may exert a direct effect on nox4 to stimulate hypertrophy and fibronectin expression or indirectly via the release of other mediators such as ang ii and/or transforming growth factor beta.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0we have shown previously that ang ii induces protein synthesis and hypertrophy via nox4 in mcs 27 28 .
9958RENreninrenin1.0thus the renin angiotensin system may contribute to the stimulation of nox4 based nad p h oxidase activity.
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p47 protein1.0this hypothesis is supported by the observation that ros generation and nad p h oxidase subunit p47 protein expression were increased in glomeruli of rats with type 1 diabetes effects that were inhibited by treatment with angiotensin converting enzyme inhibitor or ang ii type 1 at 1 receptor blocker 13 .
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0on and nad p h oxidase subunit p47 protein expression were increased in glomeruli of rats with type 1 diabetes effects that were inhibited by treatment with angiotensin converting enzyme inhibitor or ang ii type 1 at 1 receptor blocker 13 .
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1angiotensin converting enzyme1.0ported by the observation that ros generation and nad p h oxidase subunit p47 protein expression were increased in glomeruli of rats with type 1 diabetes effects that were inhibited by treatment with angiotensin converting enzyme inhibitor or ang ii type 1 at 1 receptor blocker 13 .
9958RENreninrenin1.0high glucose concentration enhances ang ii generation via up regulation of angiotensinogen angiotensin converting enzyme or renin in renal cells including mcs 59 .
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0high glucose concentration enhances ang ii generation via up regulation of angiotensinogen angiotensin converting enzyme or renin in renal cells including mcs 59 .
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1angiotensin converting enzyme1.0high glucose concentration enhances ang ii generation via up regulation of angiotensinogen angiotensin converting enzyme or renin in renal cells including mcs 59 .
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensinogen1.0high glucose concentration enhances ang ii generation via up regulation of angiotensinogen angiotensin converting enzyme or renin in renal cells including mcs 59 .
391AKT1v-akt murine thymoma viral oncogene homolog 1protein kinase b1.0 cell; as phosphorothioated antisense oligonucleotides; ng normal glucose; hg high glucose; dcf 2' 7' dichlorodihydrofluorescein; ang ii angiotensin ii; erk extracellular signal regulated kinase; pkb protein kinase b; stz streptozotocin; rlu relative light units; pbs phosphate buffered saline; bsa bovine serum albumin.
399ALBalbuminserum albumin1.0lorodihydrofluorescein; ang ii angiotensin ii; erk extracellular signal regulated kinase; pkb protein kinase b; stz streptozotocin; rlu relative light units; pbs phosphate buffered saline; bsa bovine serum albumin.
6871MAPK1mitogen-activated protein kinase 1extracellular signal regulated kinase1.0ecies; nox4 nad p h oxidase 4; mc mesangial cell; as phosphorothioated antisense oligonucleotides; ng normal glucose; hg high glucose; dcf 2' 7' dichlorodihydrofluorescein; ang ii angiotensin ii; erk extracellular signal regulated kinase; pkb protein kinase b; stz streptozotocin; rlu relative light units; pbs phosphate buffered saline; bsa bovine serum albumin.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)ang ii1.0thy; ros reactive oxygen species; nox4 nad p h oxidase 4; mc mesangial cell; as phosphorothioated antisense oligonucleotides; ng normal glucose; hg high glucose; dcf 2' 7' dichlorodihydrofluorescein; ang ii angiotensin ii; erk extracellular signal regulated kinase; pkb protein kinase b; stz streptozotocin; rlu relative light units; pbs phosphate buffered saline; bsa bovine serum albumin.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensin ii1.0s reactive oxygen species; nox4 nad p h oxidase 4; mc mesangial cell; as phosphorothioated antisense oligonucleotides; ng normal glucose; hg high glucose; dcf 2' 7' dichlorodihydrofluorescein; ang ii angiotensin ii; erk extracellular signal regulated kinase; pkb protein kinase b; stz streptozotocin; rlu relative light units; pbs phosphate buffered saline; bsa bovine serum albumin.