Nox and renal disease

Holterman, Chet E.; Read, Naomi C.; Kennedy, Carol

doi:10.1042/cs20140361

Cited by 76 publications

(73 citation statements)

References 155 publications

(198 reference statements)

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“…The NOX family is believed to be one of the major oxidases regulating ROS production in DN (45,46). NOX4 is a crucial isoform contributing to DN, because the deficiency of NOX1 and NOX2 has no effect on the albuminuria and renal fibrosis in diabetic animals (47,48).…”

Section: Discussionmentioning

confidence: 99%

Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Cheng

Ding

et al. 2016

Diabetes

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Peroxisome proliferator–activated receptor-α (PPARα) displays renoprotective effects with an unclear mechanism. Aberrant activation of the canonical Wnt pathway plays a key role in renal fibrosis. Renal levels of PPARα were downregulated in both type 1 and type 2 diabetes models. The PPARα agonist fenofibrate and overexpression of PPARα both attenuated the expression of fibrotic factors, and suppressed high glucose–induced or Wnt3a-induced Wnt signaling in renal cells. Fenofibrate inhibited Wnt signaling in the kidney of diabetic rats. A more renal prominent activation of Wnt signaling was detected both in PPARα−/− mice with diabetes or obstructive nephropathy and in PPARα−/− tubular cells treated with Wnt3a. PPARα did not block the transcriptional activity of β-catenin induced by a constitutively active mutant of lipoprotein receptor–related protein 6 (LRP6) or β-catenin. LRP6 stability was decreased by overexpression of PPARα and increased in PPARα−/− tubular cells, suggesting that PPARα interacts with Wnt signaling at the Wnt coreceptor level. 4-Hydroxynonenal–induced reactive oxygen species production, which resulted in LRP6 stability, was suppressed by overexpression of PPARα and dramatically enhanced in PPARα−/− tubular cells. Diabetic PPARα−/− mice showed more prominent NADPH oxidase-4 overexpression compared with diabetic wild-type mice, suggesting that the inhibitory effect of PPARα on Wnt signaling may be ascribed to its antioxidant activity. These observations identified a novel interaction between PPARα and the Wnt pathway, which is responsible, at least partially, for the therapeutic effects of fenofibrate on diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Cheng

Ding

et al. 2016

Diabetes

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“…How can these contradictory findings be reconciled? To solve this riddle, a biphasic model has been proposed (81). According to this, limited early Nox4-mediated ROS production may be protective because, presumably through Nrf2 and Hif1␣, it may induce antioxidant genes (80).…”

Section: Discussionmentioning

confidence: 99%

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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“…Among potential sources of ROS, NOX1, NOX2 and NOX4 are the major ROS producing oxidases in the kidney [71][72][73][74]. However, the mechanism of how these enzymes are regulated upon tissue injury and inflammation and how they might contribute to inflammatory signaling is not completely understood.…”

Section: Ros-dependent Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

et al. 2016

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Biglycan, a ubiquitous proteoglycan, acts as a danger signal when released from the extracellular matrix. As such, biglycan triggers the synthesis and maturation of interleukin-1β (IL-1β) in a Toll-like receptor (TLR) 2-, TLR4-, and reactive oxygen species (ROS)-dependent manner. Here, we discovered that biglycan autonomously regulates the balance in IL-1β production in vitro and in vivo by modulating expression, activity and stability of NADPH oxidase (NOX) 1, 2 and 4 enzymes via different TLR pathways. In primary murine macrophages, biglycan triggered NOX1/4-mediated ROS generation, thereby enhancing IL-1β expression. Surprisingly, biglycan inhibited IL-1β due to enhancement of NOX2 synthesis and activation, by selectively interacting with TLR4. Synthesis of NOX2 was mediated by adaptor molecule Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF). Via myeloid differentiation primary response protein (MyD88) as well as Rac1 activation and Erk phosphorylation, biglycan triggered translocation of the cytosolic NOX2 subunit p47(phox) to the plasma membrane, an obligatory step for NOX2 activation. In contrast, by engaging TLR2, soluble biglycan stimulated the expression of heat shock protein (HSP) 70, which bound to NOX2, and consequently impaired the inhibitory function of NOX2 on IL-1β expression. Notably, a genetic background lacking biglycan reduced HSP70 expression, rescued the enhanced renal IL-1β production and improved kidney function of Nox2(-/y) mice in a model of renal ischemia reperfusion injury. Here, we provide a novel mechanism where the danger molecule biglycan influences NOX2 synthesis and activation via different TLR pathways, thereby regulating inflammation severity. Thus, selective inhibition of biglycan-TLR2 or biglycan-TLR4 signaling could be a novel therapeutic approach in ROS-mediated inflammatory diseases.

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Nox and renal disease

Cited by 76 publications

References 155 publications

Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

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