doi: 10.1161/CIRCRESAHA.107.158295
© 2007 American Heart Association, Inc.
Editorials |
Endothelial NF-
B As a Mediator of Kidney Damage
The Missing Link Between Systemic Vascular and Renal Disease?
From the Emory University Division of Cardiology, Department of Medicine, Atlanta, Ga; and the Atlanta Veterans Administration Hospital, Ga.
Correspondence to David G. Harrison, Division of Cardiology, Emory University, 101 Woodruff Circle, WMBR 319, Atlanta, GA 30322. E-mail dharr02{at}emory.edu
See related article, page 268–276
Key Words: molecular biology • monocytes • monocyte chemoattractant protein-1 • nitric oxide • NF-
B • oxidative stress
In the current issue of Circulation Research Henke and coworkers demonstrate a critical role for the transcription factor nuclear factor-kappaB (NF-B) in the genesis of renal damage caused by hypertension.1 The authors created mice in which the NF-B superrepressor IB
N was induced in the endothelium using Cre/Lox technology. They then exposed these mice and appropriate controls to a rather complex model of hypertension involving angiotensin II infusion, high salt and inhibition of endogenous nitric oxide production. Although the NF-B superrepressor did not prevent hypertension, it markedly diminished renal injury. Albuminuria in the NF-B suppressed mice was reduced by half, perivascular and tubular fibrosis was decreased, TNF- levels were diminished and the renal infiltration of inflammatory cells reduced. The study illustrates a previously unappreciated role of the endothelium and specifically endothelial NF-B in coordinating numerous aspects of hypertensive renal damage.
Prevention of hypertension and its attendant end organ damage is one of the major therapeutic aims in cardiovascular medicine. A vast amount of research has been devoted to understanding the mechanisms and pathogenesis of hypertension, but for the past two decades this knowledge has not led to new treatments. Although current drugs are effective in many patients, there are still numerous patients in whom even combination therapies are not successful.2 Moreover while we focus almost solely on bringing the blood pressure levels back to normal, the mechanisms of end-organ damage are in part independent of blood pressure and are influenced by factors such as race, socioeconomic status, diabetes, dyslipidemia and other unknown factors. This is particularly true of renal failure, which occurs much more commonly in blacks and is exacerbated by diabetes.
Hypertensive end organ damage is predominantly caused by inflammatory cells such as macrophages and lymphocytes infiltrating target organs. Numerous aspects of the hypertensive milieu, including altered mechanical forces, increased angiotensin II, elevated aldosterone and locally produced cytokines seem to stimulate this process, in large part via increasing local levels of cellular adhesion molecules and chemokines, which in turn promote rolling, adhesion and penetration of inflammatory cells.3 Angiotensin II directly acts on T cells and monocytes and leads to their activation, proliferation, and promotes their migration into target organs.4 When these events occur in the vessel they predispose to atherosclerosis; in the heart, they lead to myocardial fibrosis and diastolic dysfunction; and in the kidney they cause albuminuria, progressive renal damage and ultimately renal insufficiency. Given the multiorgan nature of these insults, hypertension must be viewed as a systemic inflammatory process.
Although each of the organs mentioned above are composed of numerous different cells types, all of which might participate in the inflammatory process, the endothelial cell plays a central role because it serves as the interface between the circulating inflammatory cells and the target organs. A critical signaling event leading to endothelial cell inflammation is activation of the NF-B family of transcription factors. These fascinating Rel family proteins proteins exist in the cytoplasm of mammalian cells in an inactive state as heterotrimers, generally consisting of an inhibitory subunit, IB and two other proteins including p50, p65 (Rel A), Rel B and c-Rel.5 When the cell is activated by diverse proinflammatory stimuli, including cytokines, endotoxin, modified lipids and reactive oxygen species the upstream I-kappa kinase (IK) is activated. IK in turn phosphorylates IB and targets it for proteosomal degradation (Figure).5 The released dimer, most commonly the p50/p65 heterodimer, then translocates to the nucleus where it binds to the promoters of a variety of genes.5 In general, this leads to expression of proinflammatory molecules such as the vascular cell adhesion molecule-1 (VCAM-1), the intracellular adhesion molecule-1 (ICAM-1), the monocyte chemoattractant peptide 1 (MCP-1), interleukin-6 and many others.5 Depending on the cell type, NF-B activation can lead to cell specific inflammatory responses. For example, in the T cell, NF-B activation occurs as a consequence of T cell signaling via the immunological synapse and leads to T cell activation and polarization.6 Because of these myriad roles, NF-B can be considered a concertmaster in orchestrating intracellular and intercellular inflammatory events (Figure).5
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Although NF-B is generally viewed detrimental in the pathogenesis of cardiovascular disease, it can also have protective roles. A recent study has shown that cytoprotective molecules such as the manganese superoxide dismutases, Bcl2 and GADD45ß can be induced by NF-B in endothelial cells exposed to laminar shear.7 The increase in eNOS in response to shear stress is mediated by NF-B, at least at early time points. It is therefore incorrect to conclude that all consequences of NF-B activation are deleterious.
It should be noted that Henke et al used a "triple hit" model of hypertension involving angiotensin II infusion, high salt and inhibition of NO synthesis that would seem particularly prone to activate NF-B. Each of these insults has been shown to independently activate NF-B and together likely work synergistically to do so. In particular NO inhibits NF-B activation via at least two mechanisms.8 First, NO is a potent stimulus for increasing IB expression, which sequesters the p50/p65 heterodimers. Second, NO reacts with a critical cysteine in p50. Together, these effects of NO prevent nuclear translocation of the active subunits and inhibit expression of inflammatory molecules like VCAM-1, MCP-1 and ICAM-1.9,10,11 Likewise, angiotensin II, via its activation of the NADPH oxidase, can increase production of reactive oxygen species that oxidatively inactivate NO and also can directly activate NF-B via redox sensitive mechanisms. The combination of these insults permitted Henke et al to observe renal damage in a relatively short time, however it is likely that the individual insults lead to renal damage over a longer period of time.
Importantly, the extracellular factors that activate NF-B are only recently being characterized. It has been demonstrated that exposure of human aortic endothelial cells to triglycerides from subjects in the postprandial state markedly augments the activation of NF-B caused by cytokines.12 It is possible that these proatherogenic triglycerides predispose to renal injury via activation of NF-B in the kidney. Of note, fibrates, commonly used for treatment of lipid disorders, also prevent NF-B activation.13 Related to the study by Henke et al, these agents have been shown to prevent renal damage in hypertensive transgenic rats and to prevent progression of microalbuminuria in the DAIS trial involving diabetic subjects.14 Moreover, the VA HIT trial showed a substantial benefit of the fibrate gemfibrozil, beyond what could be expected based on changes in lipids caused by these drugs.15 It is interesting to speculate that some of this covert beneficial effect was because of inhibition of NF-B.
The considerations above raise the possibility that other drugs that inhibit NF-B would be useful in preventing renal damage. A number of NF-B inhibitors have been developed including panoxypanadone, pyrolidine dithiodicarbamate (PDTC), dehdyroxy-methylepoxyquinomycin (DHMEQ) and SP100030.16,17 These are not currently used clinically although some have been used in experimental animals. Drugs such as BMS34554118 and curcumin,19 which respectively inhibit IK and the coactivating factor p300, have also been used to prevent NF-B activation and might prove beneficial in the prevention of renal damage in the setting of hypertension. Likewise, statins and the insulin sensitizing agent metformin have also been shown to inhibit NF-B.20
The study by Henke et al might also provide insight into frequent occurrence of renal failure in patients with systemic atherosclerosis. Death from cardiovascular causes occurs in 50% of patients with renal failure and is 20-fold more prevalent than in those without renal failure.21 Individuals with renal failure in need of but prior to dialysis have markedly thickened carotid intimal medial thickness, a surrogate for systemic atherosclerosis, and this is independent of other traditional risk factors including age and blood pressure.22 Activation of NF-B by factors like those studied by Henke et al occurs in systemic vessels and promotes the inflammatory response typical of atherosclerosis. In keeping with this, p50 and p65 are present in the nuclei of vascular smooth cells in human atheroma but not in normal vascular smooth muscle cells.23 The NF-B inhibitor DHMEQ reduces atherosclerosis Apo(E)-deficient mice.24 Moreover, polymorphisms that reduce expression of A20, a negative regulator of NF-B, increase atherosclerosis in diabetics by 4-fold.24 Physicians are often baffled by the unexplained relentless progression of renal failure in their patients with atherosclerosis. It is very possible that this represents a state of systemic inflammation that not only affects large vessels but also the kidneys.
In conclusion, the study by Henke et al emphasizes the role of NF-B as a major player in modulating the renal effects of hypertension. The interactions between cytokines, triglycerides, angiotensin II, altered mechanical forces and other factors that lead to endothelial NF-B activation almost certainly link hypertension, systemic atherosclerosis and the progressive renal failure commonly observed clinically. As such this transcription factor is clearly a very important therapeutic target, keeping in mind that not all NF-B is bad.
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Acknowledgments |
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Sources of Funding
This work was supported by National Institutes of Health (NIH) grant HL39006, NIH program project grants HL58000 and HL075209, and a Department of Veterans Affairs merit grant.
Disclosures
D.G.H. is a consultant for Novartis and Merck.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Related Article:
B Suppression Attenuates Hypertension-Induced Renal Damage
Circ. Res. 2007 101: 268-276.
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