Endothelial NF-κB As a Mediator of Kidney Damage

Abstract

See related article, page 268–276 In the current issue of Circulation Research Henke and coworkers demonstrate a critical role for the transcription factor nuclear factor-kappaB (NF-κB) in the genesis of renal damage caused by hypertension.1 The authors created mice in which the NF-κB superrepressor IκBαΔN 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-κB superrepressor did not prevent hypertension, it markedly diminished renal injury. Albuminuria in the NF-κB suppressed mice was reduced by half, perivascular and tubular fibrosis was decreased, TNF-α 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-κB 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 …