Role of Nox4 in murine models of kidney disease

Bábelová, Andrea; Avaniadi, Despina; Jung, Ok‐Sang; Fork, Christian; Beckmann, Janet; Kosowski, Judith; Weißmann, Norbert; Anilkumar, Narayana; Shah, Ajay M.; Schaefer, Liliana; Schröder, Katrin; Brandes, Ralf P.

doi:10.1016/j.freeradbiomed.2012.06.027

Cited by 134 publications

(123 citation statements)

References 40 publications

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“…Although most studies found increased renal Nox4 expression during chronic injury (27,86,87), progressive loss was also reported (35). We found that epithelial Nox4 increases during UUO as detected by immunofluorescence as well as by qPCR performed on tubular samples obtained by laser capture microdissection.…”

Section: Discussionmentioning

confidence: 46%

“…One study found that Nox4 deletion indeed mitigated the progression of DKD on the apoE Ϫ/Ϫ background (29). However, Babelova et al (35) using four chronic kidney injury models detected no protective effect of Nox4 deletion; in fact, they reported slight deterioration of obstructive nephropathy. Similar results were obtained in another study, claiming that Nox4 protects against kidney fibrosis (80).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the vast majority of the literature has examined the regulation of Nox4 expression in vascular smooth muscle, endothelium, and fibroblasts, although information in the epithelium is scarce, despite the fact that the tubules were reported to possess 80% of all Nox4 activity in the kidney (35). Two additional reasons lend importance to the epithelial context, namely, the epithelium differs from the other tissues both in terms of the stimuli required for Nox4 induction and in terms of the ensuing (patho)physiological consequences (see below).…”

Section: Discussionmentioning

confidence: 99%

“…The rabbit polyclonal MRTF antibody (BSAC) has been described previously (34). Given the concerns regarding the specificity of commercially available Nox4 antibodies and the variability of batches (35), experiments were completed only with antibodies that recognized a protein of the proper molecular weight and of which immunoreactivity was lost upon Nox4 siRNA treatment.…”

Section: Methodsmentioning

confidence: 99%

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Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

Rozycki

Bialik

Speight

et al. 2016

Journal of Biological Chemistry

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Background: Generation of myofibroblasts, the culprit of fibrosis, requires cytoskeleton remodeling and Nox4 (NADPH oxidase) expression. The link between these events is unknown. Results: Down-regulation/inhibition of the cytoskeleton-controlled transcriptional coactivators, myocardin-related transcription factor (MRTF), and TAZ/YAP abrogates Nox4 expression. Conclusion: MRTF and TAZ/YAP are essential for Nox4 expression. Significance: We show new mechanisms whereby the cytoskeleton regulates cellular redox state and fibrogenesis.

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

Rozycki

Bialik

Speight

et al. 2016

Journal of Biological Chemistry

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“…Deletion of either Nox4 or -2 in STZ-induced diabetes is not beneficial and may even be deleterious in the case of Nox4, supporting studies showing that Nox4 may play a protective role in chronic kidney injury and endothelial dysfunction. [43][44][45][46] However, the role of Nox4 remains controversial in the diabetic setting, because short-term pharmacological Nox4 inhibition reduces renal ROS generation, glomerular hypertrophy, and fibronectin expression. 42 Unlike other Nox family members, nothing is known regarding the function of Nox5 in animal models of disease, owing mainly to its absence from the mouse and rat genome.…”

Section: Discussionmentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

Journal of the American Society of Nephrology

117

122

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NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5 pod+ ). Nox5 pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5 pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension. Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier. 1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction. Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important. [3][4][5][6] Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the

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Dexmedetomidine alleviates lipopolysaccharide‐induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway

Yao

Feng

et al. 2019

J of Cellular Biochemistry

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Dexmedetomidine (DEX) prevents kidney damage caused by sepsis, but the mechanism of this effect remains unclear. In this study, the protective molecular mechanism of DEX in lipopolysaccharide (LPS)‐induced acute kidney injury was investigated and its potential pharmacological targets from the perspective of inhibiting oxidative stress damage and the nucleotide‐binding domain‐like receptor protein 3 (NLRP3) inflammasome activation. Intraperitoneal injection of DEX (30 μg/kg) significantly improved LPS (10 mg/kg) induced renal pathological damage and renal dysfunction. DEX also ameliorated oxidative stress damage by reducing the contents of reactive oxygen species, malondialdehyde and hydrogen peroxide, and increasing the level of glutathione, as well as the activity of superoxide dismutase and catalase. In addition, DEX prevented nuclear factor‐kappa B (NF‐κB) activation and I‐kappa B (IκB) phosphorylation, as well as the expressions of NLRP3 inflammasome‐associated protein and downstream IL‐18 and IL‐1β. The messengerRNA (mRNA) and protein expressions of toll‐like receptor 4 (TLR4), NADPH oxidase‐4 (NOX4), NF‐κB, and NLRP3 were also significantly reduced by DEX. Their expressions were further evaluated by immunohistochemistry, yielding results were consistent with the results of mRNA and protein detection. Interestingly, the protective effects of DEX were reversed by atipamezole‐an alpha 2 adrenal receptor (α2AR) inhibitor, whereas idazoxan‐an imidazoline receptor (IR) inhibitor failed to reverse this change. In conclusion, DEX attenuated LPS‐induced AKI by inhibiting oxidative stress damage and NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway, mainly acting on the α2AR rather than IR.

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Role of Nox4 in murine models of kidney disease

Cited by 134 publications

References 40 publications

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Dexmedetomidine alleviates lipopolysaccharide‐induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway

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