NOX4 is an enigmatic member of the NOX (NADPH oxidase) family of ROS (reactive oxygen species)-generating NADPH oxidases. NOX4 has a wide tissue distribution, but the physiological function and activation mechanisms are largely unknown, and its pharmacology is poorly understood. We have generated cell lines expressing NOX4 upon tetracycline induction. Tetracycline induced a rapid increase in NOX4 mRNA (1 h) followed closely (2 h) by a release of ROS. Upon tetracycline withdrawal, NOX4 mRNA levels and ROS release decreased rapidly ( 100 muM). The pattern of NOX4-dependent ROS generation was unique: (i) ROS release upon NOX4 induction was spontaneous without need for a stimulus, and (ii) the type of ROS released from NOX4-expressing cells was H(2)O(2), whereas superoxide (O(2)(-)) was almost undetectable. Probes that allow detection of intracellular O(2)(-) generation yielded differential results: DHE (dihydroethidium) fluorescence and ACP (1-acetoxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine) ESR measurements did not detect any NOX4 signal, whereas a robust signal was observed with NBT. Thus NOX4 probably generates O(2)(-) within an intracellular compartment that is accessible to NBT (Nitro Blue Tetrazolium), but not to DHE or ACP. In conclusion, NOX4 has a distinct pharmacology and pattern of ROS generation. The close correlation between NOX4 mRNA and ROS generation might hint towards a function as an inducible NOX isoform.

/pdf/nox4-activity-is-determined-by-mrna-levels-and-reveals-a-34mrli7eh2.pdf

NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation

Molecular mechanisms underlying renal complications of diabetes remain unclear. We tested whether renal NADPH oxidase (Nox) 4 contributes to increased reactive oxygen species (ROS) generation and hyperactivation of redox-sensitive signaling pathways in diabetic nephropathy. Diabetic mice (db/db) (20 wk) and cultured mouse proximal tubule (MPT) cells exposed to high glucose (25 mmol/l, D-glucose) were studied. Expression (gene and protein) of Nox4, p22(phox), and p47(phox), but not Nox1 or Nox2, was increased in kidney cortex, but not medulla, from db/db vs. control mice (db/m) (P < 0.05). ROS generation, p38 mitogen-activated protein (MAP) kinase phosphorylation, and content of fibronectin and transforming growth factor (TGF)-β1/2 were increased in db/db vs. db/m (P < 0.01). High glucose increased expression of Nox4, but not other Noxes vs. normal glucose (P < 0.05). This was associated with increased NADPH oxidase activation and enhanced ROS production. Nox4 downregulation by small-interfering RNA and inhibition of Nox4 activity by GK-136901 (Nox1/4 inhibitor) attenuated d-glucose-induced NADPH oxidase-derived ROS generation. High d-glucose, but not l-glucose, stimulated phosphorylation of p38MAP kinase and increased expression of TGF-β1/2 and fibronectin, effects that were inhibited by SB-203580 (p38MAP kinase inhibitor). GK-136901 inhibited d-glucose-induced actions. Our data indicate that, in diabetic conditions: 1) renal Nox4 is upregulated in a cortex-specific manner, 2) MPT cells possess functionally active Nox4-based NADPH, 3) Nox4 is a major source of renal ROS, and 4) activation of profibrotic processes is mediated via Nox4-sensitive, p38MAP kinase-dependent pathways. These findings implicate Nox4-based NADPH oxidase in molecular mechanisms underlying fibrosis in type 2 diabetic nephropathy.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00028.2010

Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy.

The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma.

Surgery is of paramount importance in the management of solid tumors as definitive resection can be totally curative. Nonetheless, metastatic recurrence after surgery remains a major cause of morbidity and mortality. Interest in the impact of the perioperative period on cancer recurrence is now growing rapidly, with recent research suggesting that some anesthetics or anesthetic techniques may influence the pathophysiology of postoperative metastatic spread. Our review examines the most widely postulated mechanisms for this, including the impact of anesthesia on neuroendocrine and immune function. We also consider evidence for a direct impact on tumor cell signaling pathways based on findings from organ protection research. These studies have demonstrated that certain volatile anaesthetics confer cytoprotective properties to exposed cells and lead to significant upregulation of Hypoxia Inducible Factor-1α (HIF-1α). This ubiquitous transcription factor exerts many effects in cancer: its activity has been linked with more aggressive phenotypes and poorer clinical prognosis. It is proposed that such an upregulation of HIFs in tumor cells by these anesthetics may contribute to a tumor's recurrence by stimulating cytoprotective or protumorigenic behavior in residual cells. Conversely, other anesthetic agents appear to downregulate HIFs or cause negligible effect and thus may prove more suitable for use in cancer surgery. As anesthetic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastases, there is an urgent need to determine the most appropriate anesthetic strategy for surgical oncology so that the optimal techniques are used to maximize long-term survival.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.26448

Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents*

Oxidative stress, mainly contributed by reactive oxygen species (ROS), has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-β pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS-generating NADPH oxidases (NOX) is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents.

Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

Most sporadically occurring renal tumors include a functional loss of the tumor suppressor VHL. Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor HIF-2α, a master transcriptional regulator of genes that drive diverse processes including angiogenesis, proliferation and anaerobic metabolism. In determining the critical functions for HIF-2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF-2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade.

https://cancerres.aacrjournals.org/content/canres/74/13/3501.full.pdf

NADPH Oxidase NOX4 Supports Renal Tumorigenesis by Promoting the Expression and Nuclear Accumulation of HIF2α

Inactivation of the von Hippel-Lindau tumor suppressor (VHL) is an early event in >60% of sporadic clear cell renal cell carcinoma (RCC). Loss of VHL E3 ubiquitin ligase function results in accumulation of the alpha-subunit of the hypoxia-inducible heterodimeric transcription factor (HIF-alpha) and transcription of an array of genes including vascular endothelial growth factor, transforming growth factor-alpha, and erythropoietin. Studies have shown that HIF-alpha can be alternatively activated by reactive oxygen species. Nox4 is an NADP(H) oxidase that generates signaling levels of superoxide and is found in greatest abundance in the distal renal tubules. To determine if Nox4 contributes to HIF activity in RCC, we examined the impact of Nox4 expression on HIF-alpha expression and transactivation. We report here that small inhibitory RNA (siRNA) knockdown of Nox4 in 786-0 human renal tumor cells expressing empty vector (PRC) or wild-type VHL (WT) results in 50% decrease in intracellular reactive oxygen species as measured by a fluorescent 2',7'-dichlorofluorescin diacetate assay, and >85% reduction in HIF2-alpha mRNA and protein levels by quantitative reverse transcription-PCR and Western blot analysis. Furthermore, expression of the HIF target genes, vascular endothelial growth factor, transforming growth factor-alpha, and Glut-1 was abrogated by 93%, 74%, and 99%, respectively, after stable transfection with Nox4 siRNA relative to nontargeting siRNA, as determined by quantitative reverse transcription-PCR. Thus, renal Nox4 expression is essential for full HIF2-alpha expression and activity in 786-0 renal tumor cells, even in the absence of functional VHL. We propose the use of Nox4 as a target in the treatment of clear cell RCC.

/pdf/nox4-is-critical-for-hypoxia-inducible-factor-2-alpha-2ig3focrpz.pdf

Nox4 Is Critical for Hypoxia-Inducible Factor 2-alpha Transcriptional Activity in Von Hippel-Lindau-deficient Renal Cell Carcinoma

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NADPH Oxidase NOX4 Supports Renal Tumorigenesis by Promoting the Expression and Nuclear Accumulation of HIF2α

Nox4 Is Critical for Hypoxia-Inducible Factor 2-alpha Transcriptional Activity in Von Hippel-Lindau-deficient Renal Cell Carcinoma