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Nitric Oxide and Mechanisms of Redox Signaling

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

Correspondence to Dr. Josef Pfeilschifter, Pharmazentrum Frankfurt, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Phone: 49-069-6301-6950; Fax: 49-069-6301-7942;

	Abstract

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
ABSTRACT. Regulation of signal transduction and gene expression is a multifaceted process involving ligands, receptors, and second messengers that trigger cascades of protein kinases and phosphatases and propagate the signal to the nucleus to alter gene expression. Reduction-oxidation (redox)-based regulatory pathways provide additional means of gating signal transduction, and redox-based regulation of gene expression emerges as a fundamental regulatory mechanism in living cells. The cellular redox state is reflected by the degree of oxidation (or reduction) of various redox-active molecules at a specific cellular location at any given time point. The ratio of oxidized/reduced redox species determines the redox potential, which may vary dramatically in time and in different compartments of a cell and consequently alter in a temporally and spatially dynamic process the activity of signaling enzymes that carry redox-active functional groups. Generation and action of free radicals such as nitric oxide, superoxide, and H₂O₂ that paradigmatically highlight the impact of redox regulation on cellular signal transduction and gene expression are discussed with a special focus on the renal glomerular response to injury. E-mail: Pfeilschifter@em.uni-frankfurt.de

	Introduction

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
The clinical characteristics of acute inflammation are familiar to anyone who has experienced a burned or infected finger. The account comprises the cardinal (main) symptoms of inflammation with heat, redness, and painful swelling that were reported by the Roman encyclopedist Celsus as calor, rubor, tumor, and dolor. Galen of Pergamon added an additional sign of inflammation: the impaired function, or functio laesa. Although unpleasant, these signs are indicators of useful processes going on with the aim of limiting tissue damage and infection and initiating repair.

Today, inflammation is an intellectually challenging problem involving cascades of signaling events and expression of inducible enzyme systems and mediators to constitute a delicate balance between local offensive and defensive factors that finally determine the outcome of the disease process: progression or resolution (1). The advent of anticytokine strategies and of inhibitors of cytokine-inducible enzyme systems and their introduction into clinical practice has rendered inflammation research fashionable and—this also needs mentioning—profitable again. The inflammatory response is a complex and tightly regulated sequence of events that starts with an initial production of proinflammatory mediators that recruit professional cells to clear the offending trigger. This is followed by an anti-inflammatory phase in which resident cells, located mainly in the mesangial cells of the renal glomerulus, may acquire the potential for protecting themselves from further activation and injury (2). The orchestration of this complex, temporally and spatially dynamic process is essential for a sophisticated orderly process of repair, the ideal outcome of inflammation. However, in many diseases, the consequences of inflammation persist with structural and functional alterations of tissues that may lead to progression and scarring (1–4).

Endogenous free radicals are thought to play decisive roles in renal diseases (3–6). They are generated as accidental by-products of aerobic energy metabolism, as cytotoxic defense mechanism of immune cells, and through the action of environmental compounds. The key radical species are nitric oxide (NO), superoxide (O₂^-), and hydrogen peroxide (H₂O₂).

Redox regulation of cellular functions is mainly due to ultimate effects in gene expression. In the past few years, a great body of experimental evidence indicated that these adaptive responses are achieved through modulation of signaling cascades and transcription factors activity (7–11).

	NO Signaling

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
In recent years, NO, a gas previously considered a noxious chemical, has become established as a diffusible universal messenger mediating cell–cell communication throughout the body (12). Under physiologic conditions, cells produce only small amounts of NO by the constitutive neuronal and endothelial NO synthase (NOS) isoforms, and only trace amounts of reactive oxygen species (ROS) are available to scavenge NO, thus indicating that direct NO chemistry will dictate functional cell responses (13). Physiologically the most relevant action of NO is the activation of the soluble guanylate cyclase. Moreover, NO can scavenge O₂^- and other free radicals and also inhibits O₂^--driven Fenton reaction and lipid peroxidation. By contrast, large amounts of NO as generated by the inducible NOS isoform in an inflammatory setting, often accompanied by a large production of ROS, will shift NO chemistry toward indirect effects such as nitrosation, nitration, and oxidation (7,9,13). The interaction of NO with molecular oxygen (O₂) or O₂^- gives rise to the formation of the potent nitrosating agent N₂O₃ and peroxynitrite (ONOO^-), respectively. In addition, S-nitrosothiol adducts are formed by the interaction between N₂O₃ and certain protein thiol groups and evoke signaling by altering protein kinases and phosphatases, G-proteins, ion channels, protein tyrosine kinases, and redox-sensitive transcription factors such as nuclear factor B (NF-B), activator protein 1 (AP 1), or CAAT/enhancer binding protein (C/EBP) (4,7,9). ROS, most notably O₂^- and H₂O₂, are constantly formed in aerobic organisms during normal metabolism. In analogy to NO, high amounts of ROS produced by professional immune effector cells constitute important facets of defense mechanisms, whereas lower amounts generated by other cell types, including mesangial cells, serve as intracellular second messengers. When the concentration of ROS produced exceeds the cellular capacity to cope with them, oxidative stress results. ROS are generated most prominently by xanthine oxidase, cyclooxygenases, lipoxygenases, cytochrome P450 oxidases, NOS, the mitochondrial respiratory chain, and NADPH oxidases. A phagocyte-type oxidase has been postulated to operate in the kidney as an oxygen sensor and a kidney-specific NADPH oxidase or renox (now renamed Nox4) recently has been cloned and characterized (14).

The targets of ROS action have been poorly characterized and may comprise members of the classical mitogen-activated protein kinase cascade as well as the c-Jun N-terminal protein kinase pathway. Moreover, tyrosine phosphatases and the small guanosine 5'-triphosphate–binding proteins Ras and Rac1 are targeted by ROS in a redox-dependent manner (11).

	Transcriptional Regulation of Gene Expression by NO

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
Most physiologic situations are characterized by low output of NO, the activation of soluble guanylate cyclase, and the subsequent production of cGMP as the principal signaling messenger that will dominate cell responses. A wealth of evidence for alternative signaling cascades exists in which concentrations of NO are moderate to high. These signals operate in part through the redox-sensitive regulation of transcription factors (7–10) and gene expression (7,9) and on a more long-term basis alter the capacity of a cell to deal with stress conditions. Cross-communication with other pro-oxidant or antioxidant mediators will critically influence the fate of a cell under pathologic conditions when inducible NOS is expressed. Once primed and activated by inflammatory cytokines such as IL-1 and TNF-, most cells, including renal mesangial cells, co-produce NO and O₂^- or more generally speaking ROS. The interaction of NO and O₂^- is thought to be highly relevant to the regulation of gene expression (7,9).

As reported recently, a number of NO-regulated genes are also targeted by ROS (7). Whereas certain genes are regulated in a coordinated manner by NO and O₂^- (15,16), others are affected in a contrasting manner (17,18). The simultaneous generation of NO by many cells exposed to an inflammatory environment and the opposite effects of both radicals on certain genes may provide a genetic switch-like mechanism, with a subtle change in the O₂^-/NO ratio resulting in dramatic changes in enzyme expression.

A prominent group of target genes regulated in this way by NO and ROS are the extracellular matrix proteins and their metabolizing enzymes the matrix metalloproteinases (MMP) and plasminogen activators (PA), such as MMP-9 and t-PA (17–19), and their endogenous inhibitors tissue inhibitors of matrix metalloproteinase-1 and plasminogen activator inhibitor-1, respectively (17,20). In the kidney, accumulation of extracellular matrix is often a hallmark of chronic disease, eventually leading to the development of glomerulosclerosis. In this context, the coordinated expression of proteases and their inhibitors by inflammatory cytokines and NO will allow the fine-tuned regulation of tissue proteolysis and protect against overwhelming tissue destruction. NO also modulates the expression of major matrix components such as collagen, fibronectin, and laminin (20,21), which may also be important for tissue remodeling in chronic inflammatory kidney diseases. Recently, NO was found to inhibit the expression of another matrix protein, secreted protein acidic and rich in cysteine (SPARC; also known as BM-40 or osteonectin) (22). The highly glycosylated SPARC protein has a variety of biologic activities, and its action as a scavenger of PDGF may be relevant in the course of glomerulonephritis. By modulating SPARC expression, NO may subsequently affect mesangial cell proliferation in the course of glomerular inflammation.

In addition, NO up- or downregulates a heterogeneous set of gene products including protective mediators, proinflammatory mediators, chemokines and cytokines, adhesion molecules, growth factors, hormones, receptors, and signaling devices (for a review, see (7)). Many of the genes targeted by NO share roles in common physiologic and pathophysiologic processes.

	Posttranscriptional Regulation of Gene Expression by NO

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
We previously had observed that NO, given either exogenously or endogenously by stimulation of inducible NOS expression, potently inhibits the mRNA steady-state levels of cytokine-induced MMP-9 in mesangial cells (17). The negative modulation of MMP-9 expression has been confirmed in other cell types and suggests a general mechanism of NO-triggered tissue remodeling (9,23,24). When testing a 1.8-kb fragment of the promoter region of the rat MMP-9 gene by reporter gene assay, we found that NO had no direct effects on cytokine-induced MMP-9 promoter activity, although the expression of many genes has been shown to be transcriptionally modulated by NO in rat MC (7).

The 3'-untranslated region of the rat MMP-9 gene bears several adenine-uracil-uracil-adenine (AUUA) motifs, allowing for a posttranscriptional regulation of MMP-9 on the level of mRNA stability. In many genes, AU-rich elements are specifically targeted by proteins of the embryonic lethal abnormal vision (ELAV)-like protein family, which has been implicated in the regulation of mRNA stability (25,26). Using actinomycin D, an inhibitor of eukaryotic gene transcription, we found that exogenous NO significantly reduced the half-life of MMP-9 mRNA (27). Similar to MMP-9, the expression of TGF-₃ is reduced by NO via destabilization of its mRNA (28). Additional experimental work is required to evaluate more precisely the molecular mechanism of posttranscriptional regulation of MMP-9 expression by NO.

Only a minor part of the genes regulated by NO seems to be targeted by cGMP-triggered signaling mechanisms (7). However, both activation and inhibition of gene expression by cGMP has been reported. In many cases, cGMP regulates gene expression at the transcriptional level, but posttranscriptional modes of regulation by cGMP have also been observed (7,29). Whatever the detail, it is clear that a critical regulatory role in gene expression is played by NO at several distinct levels.

	Posttranslational Regulation of Gene Expression by NO

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
The early and fast pathways of NO and ROS signaling depend primarily on posttranslational redox-driven modification of cellular proteins as described above. To highlight the pathophysiologic relevance of these reactions, it may suffice to provide a recent example addressing the regulation of MMP in neuronal cell death. Gu et al. (30) observed that MMP-9 activation involves S-nitrosylation of the enzyme. During cerebral ischemia, MMP-9 co-localized with neuronal NOS. Moreover, S-nitrosylation activated MMP-9 in vitro and induced apoptosis of neuronal cells, thus suggesting a role for this activation mechanisms in the pathogenesis of acute and potentially also chronic neurodegenerative disorders (30).

Another facet of NO action is added by the study of Ferrero and Torres (31), reporting that activation of protein kinase G by NO-triggered cGMP formation mediates a drop in soluble guanylate cyclase subunit mRNA levels but also by reducing ₁-subunit stability. Modulation of protein stability by NO has also been documented by Franzen et al. (32,33), who observed a proteasome-mediated degradation of neutral ceramidase in renal mesangial cells. As ceramidase is a key enzyme regulating the concentration of the lipid second messenger ceramide, this may have an important impact on cellular fidelity (32,33).

Furthermore, NO has been found to stabilize proteins such as the transcription factor hypoxia inducible factor-1 (HIF-1), which is subjected to protein stability regulation and continuously degraded under normoxic conditions. Besides hypoxia, diverse agonists including inflammatory cytokines are known to stabilize HIF-1 during normoxia (34). Zhou et al. (35) recently reported that NO and TNF-, derived from activated macrophages, provoke HIF-1 stabilization in tubular LLC-PK1 cells under normoxic conditions. This in turn will have an impact on the expression levels of hypoxia-regulated genes (36) and underscores our recent suggestion that hypoxia-induced genes partially overlap with the NO- or ROS-targeted genes (7).

	Perspectives

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 
During the past years, the most impressive progress in the treatment of chronic inflammation has been the approval of anticytokine and cyclooxygenase 2 inhibitor drugs, but despite the impressive success, the prospects of these therapeutics is not at all clear. High costs of treatment and also unwanted side effects limit the perspectives of an optimal therapy. In this regard, widely known companions have entered again center stage. Research progress in the area of redox regulation of signal transduction and gene expression has provided exciting new findings with remarkable therapeutic potential. Cellular thiol modulatory agents (37), isoenzyme-specific NOS inhibitors (38), peroxynitrite decomposing catalysts, and superoxide dismutase mimetics (39) may open doors to pharmacologic intervention in inflammatory diseases. In addition, current research strategies focusing on transcriptional and translational control mechanisms are likely to be very exciting and may provide new ways to tackle challenges in the field of inflammation in the years to come.

	Acknowledgments

 
Financial support for this work was provided by the German Research Foundation (DFG) (SFB 553, PF 361/1-1, and HU 842/2-2) and the Stiftung Verum für Verhalten und Umwelt.

	References

Top Abstract Introduction NO Signaling Transcriptional Regulation of... Posttranscriptional Regulation... Posttranslational Regulation of... Perspectives References

 

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