Vascular Endothelial Cell–Specific NF-κB Suppression Attenuates Hypertension-Induced Renal Damage

Abstract

Abstract-Nuclear factor kappa B (NF-B) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-B suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-B super-repressor IB␣⌬N (Tie-1-⌬N mice) overexpression. We confirmed cell-specific IB␣⌬N expression and reduced NF-B activity after TNF-␣ stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-Larginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-⌬N and control mice. In contrast to control mice, Tie-1-⌬N mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-B targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-B activation and hypertension-induced renal damage. We conclude that in vivo NF-B suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure. Key Words: hypertension Ⅲ endothelium Ⅲ NF-B Ⅲ target-organ damage H ypertension is a risk factor for target-organ damage such as cardiac and renal disease. 1 Endothelial cell injury initiates adhesion molecule and chemokine expression promoting inflammation that contributes to the pathogenesis of hypertension-induced target organ damage. [2][3][4][5] Patients with severe hypertension and target-organ damage often show elevated angiotensin (Ang) II levels and reduced nitric oxide (NO) production. Ang II signaling blockade reduces blood pressure and blunts the development and progression of vascular disease in small and large vessels in experimental animal models and in humans. Ang II also elicits an inflammatory response in both endothelial cells 6 and vascular smooth muscle cells. 7,8 Numerous in vitro and in vivo studies demonstrated that Ang II activates the nuclear factor kappa B (NF-B), a major transcription factor in mediating inflammation and innate immunity. 4,6 -8 In resting cells, NF-B resides inactive in the cytoplasm by forming complexes with the inhibitor of B (I〉) proteins. Exposure to extracellular stimuli like TNF-␣, IL-1, reactive oxygen species, Ang II, and numerous other activators leads to rapid phosphorylation, site-specific ubiquitination, and subsequent degradation of the IB proteins by the 26S proteasome. 9 The resulting free NF-B molecules translocate to the nucleus and regulate target gene expression. The targets include genes involved in the control of cell proliferation, apoptosis, innate, and adaptive immune response. 10,11 NF-B and inflammation play an important role in the development of the target organ damage. 4,[12][13][14][15][16][17] However, inhibition of NF-B signaling could also be detrimental. 18,19 Furthermore, the ideal site for NF-B inhibition in the vesse...

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

“…Hu et al (13) demonstrated that the administration of pressor doses of L-NAME (10 g·kg Ϫ1 ·min Ϫ1 ) in combination with a small dose of ANG II (10 ng· kg Ϫ1 ·min Ϫ1 ) in rats exacerbated both the hypertension and renal injury compared with rats made hypertensive with L-NAME or ANG II alone; however, the magnitude of BP-dependent vs. BPindependent renal injury was not determined. Particularly relevant to the results of our study, Henke et al (12) reported that suppression of endothelial NF-B, a master regulatory transcription factor influencing several potential pathways of injury (i.e., oxidative stress, inflammation, etc.) attenuated renal injury in ANG IIϩL-NAME-induced hypertensive mice fed a 1% NaCl diet.…”

“…), and it has become well established that nitric oxide (NO) plays an important role to counterbalance these deleterious pathways (1). Elevated ANG II and decreased NO levels have been reported in models of diabetes, heart failure, atherosclerosis, and hypertension (1,12,19,33,38,48). It is possible that the extent of BP-independent injury induced by ANG II would be exacerbated in situations of reduced NO availability.…”

NF-kB Expression in IgA Nephropathy Outcome

“…In rats, the suppression of endothelial NF-kB, measured by IHC, showed a decrease in renal injuryinduced arterial hypertension [7]. In human renal disease, there has not been any histologic evidence of NFkB activation in vascular cells [10,11,17,22].…”

The inextricable role of the kidney in hypertension

“…This pathway seems to play a central role in blood pressure control since its blockade protects against hypertension (67). NF-κB activation within the vascular endothelium drives hypertensive renal damage without measurable effects on blood pressure suggesting a direct role in end-organ damage (68). Within cardiovascular control centers in the brain, NF-κB activation potently enhances sympathetic outflow (69)(70)(71), which could potentially promote sodium retention in the kidney via stimulation of renal sympathetic nerves.…”