IgG Receptor FcγRIIB Plays a Key Role in Obesity-Induced Hypertension

Abstract

There is a well-recognized association between obesity, inflammation, and hypertension. Why obesity causes hypertension is poorly understood. We previously demonstrated using a C-reactive protein (CRP) transgenic mouse that CRP induces hypertension that is related to NO deficiency. Our prior work in cultured endothelial cells identified the Fcγ receptor IIB (FcγRIIB) as the receptor for CRP whereby it antagonizes endothelial NO synthase. Recognizing known associations between CRP and obesity and hypertension in humans, in the present study we tested the hypothesis that FcγRIIB plays a role in obesity-induced hypertension in mice. Using radiotelemetry, we first demonstrated that the hypertension observed in transgenic mouse-CRP is mediated by the receptor, indicating that FcγRIIB is capable of modifying blood pressure. We then discovered in a model of diet-induced obesity yielding equal adiposity in all study groups that whereas FcγRIIB+/+ mice developed obesity-induced hypertension, FcγRIIB−/− mice were fully protected. Levels of CRP, the related pentraxin serum amyloid P component which is the CRP-equivalent in mice, and total IgG were unaltered by diet-induced obesity; FcγRIIB expression in endothelium was also unchanged. However, whereas IgG isolated from chow-fed mice had no effect, IgG from high-fat diet–fed mice inhibited endothelial NO synthase in cultured endothelial cells, and this was an FcγRIIB-dependent process. Thus, we have identified a novel role for FcγRIIB in the pathogenesis of obesity-induced hypertension, independent of processes regulating adiposity, and it may entail an IgG-induced attenuation of endothelial NO synthase function. Approaches targeting FcγRIIB may potentially offer new means to treat hypertension in obese individuals.

Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance

“…(17). Consistent with previous reports (23,24), we found that neither plasma CRP nor SAP was elevated by diet-induced obesity in mice (Supplemental Figure 7, A and B). However, since SAP is the acute-phase reactant pentraxin in mice and CRP is not (25,26), and, as such, SAP abundance may change earlier during the genesis of obesity, we compared the development of obesity-induced insulin resistance in SAP +/+ with that of SAP -/-mice.…”

“…However, it was entirely unknown whether FcγRIIB, CRP, the murine CRP-equivalent acute-phase reactant SAP, the classical receptor ligand IgG, or any related mechanisms participate in obesity-induced insulin resistance. A role for FcγRIIB in obesity-related disease was first demonstrated when we determined that mice globally deficient in the receptor are protected from obesity-induced hypertension (24). Although further elucidation of the processes whereby the receptor causes blood pressure elevation in obesity is required, the available evidence to date suggests that the hypertension and insulin resistance that complicate obesity may have shared mechanistic origins centered on FcγRIIB.…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…Approaches targeting FcgammaRIIB may potentially offer new means to treat hypertension in obese individuals. 79 Although antibodies seem to be important, B cells may exert their effects through B-cell specific contribution to cytokine production, such as tumor necrosis factor-α, 80 which has been shown to be prohypertensive and proatherosclerotic. Role of macrophages in hypertension and atherosclerosis is evident 67,81 and closely linked to NADPH oxidases, which are abundant within both monocytes and macrophages.…”

Fcγ Receptors in Solid Organ Transplantation

“…FcγRI and FcγRII expression on cultured human aortic endothelial cells was shown to mediate IgG internalisation, cytokine production, upregulation of adhesion molecules and activation by CRP in vitro [63]. Furthermore, FcγRIIB has been implicated in the pathogenesis of obesity-induced hypertension, via IgG-mediated attenuation of endothelial NO synthase activity [64]. The extent of FcγR expression on renal endothelial cells is less clear [65].…”