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• W2051919705 abstract "Inflammatory pathways continue to emerge as major contributors—and possibly, initiators or propagators—for a broad range of hypertensive and cardiovascular diseases. Studies of the composition of atherosclerotic plaques from aorta, coronary, and other vascular beds long have been characterized by a complex array of T and B cells, macrophages, and other cells, with a variety of epitopes linking them to adaptive and innate immunity (1). Overt vascular disease, including abdominal aortic aneurysms, carotid disease, and coronary syndromes, is known to have extensive inflammatory elements (2). Aortic disease, in particular, may be related more closely to disturbances in local metallo-proteinases and tissue inflammation than to conventional risk factors, such as dyslipidemias and hypertension (2). Although the presence of T cells seems well suited as a local response to established tissue injury and cell breakdown, recent studies suggest that inflammatory cells may participate much earlier in the process. Angiotensin-mediated pressure elevations may reflect AT1 receptor activation on T cells that may both stimulate sympathetic nerve pathways and boost chemokine expression, recruiting activated T cells to perivascular tissue (3). Local activation of NADPH oxidase by inflammatory cells induces vascular remodeling and vasoconstriction, thereby participating in the genesis of sustained hypertension (3). Simple observations that systemic markers of inflammation, such as C-reactive peptide, track closely with both arterial pressure and cardiovascular risk in entire populations add plausibility to these concepts. The role of inflammation in human renovascular disease has been far less studied. In this regard, the report by Kotliar et al. (4) in CJASN provides additional insights into inflammatory components associated with subclinical renal artery stenosis. The work by Kotliar et al. (4) undertook to characterize PBMC populations in subjects undergoing cerebral and coronary angiography during which renal angiograms were also obtained. They identified a group of patients with modest but demonstrable atherosclerotic renovascular disease and compared that group to a group with no visible angiographic disease. Patients were selected without detectable coronary or carotid lesions, with well-preserved kidney function (creatinine <1.2 mg/dl), and without microalbuminuria. They attempted to withhold antihypertensive medications recognized to affect immune cell populations for several weeks. Groups with renal arterial disease did not differ with respect to gender, age, BP levels, smoking status, numbers of drugs, and/or identified dyslipidemia. Because BP levels were controlled and levels of stenosis were mild (<50% lumen occlusion), the renal artery disease (RAD) group was presented as early atherosclerotic disease. Despite these characteristics, the distribution and prevalence of circulating CD3+, CD4+, CD83+, and CD84+ cells were substantially higher in RAD subjects compared with subjects with no identifiable renovascular involvement. No differences in S-100, CD8+, and CD25+ cell populations were identified. Interestingly, the work by Kotliar et al. (4) attempted to associate these cell population studies with postmortem renal artery tissue samples from groups of subjects dying traumatic deaths (no apparent cardiovascular cause) with identified RAD and free of RAD. These tissue samples again showed similar increases in CD3+ and CD4+ populations as well as CD83+ and CD86+ populations. CD8+ and CD25+, again, did not differ, although S-100 cells were more prominent in the tissue samples. The fact that patterns in PBMCs agreed generally with the arterial postmortem samples is presented as supportive evidence that the circulating cells indeed derive from the renal vasculature rather than from other sites. The increased proportions of CD3+, CD4+, and S-100+ cells in postmortem samples from patients with renal atherosclerotic disease compared with those patients free of disease led Kotliar et al. (4) to postulate additional homing and proliferative cellular mechanisms within the developing lesion. The initiating factor for these lesions cannot be established from these studies, but Kotliar et al. (4) speculate that this factor may relate to observations of higher density of dendritic cells found to adhere to regions with turbulent blood flow in healthy subjects (5,6). Regardless of the precise sequence, these data provide suggestive evidence that atherosclerotic renovascular disease in humans is associated with activated T cells and dendritic cell markers before tissue injury measurably extends to the kidney itself. Is it possible that activation of pressor mechanisms, such as the renin–angiotensin system, participate in accelerating vessel injury and remodeling in these patients with essential hypertension? No data regarding plasma renin activity are presented in this paper, although it is recognized that angiotensin is a potent activator of inflammation (7). Whether dendritic or T cell pathways within the vessel wall may be amenable to therapy targeted specifically to vascular inflammation cannot be addressed with the data available in this study. The work by Kotliar et al. (4) postulates that such anti-inflammatory pathways may be worth additional study. Earlier experimental studies in thymectomized mice and/or models treated with mycophenolate develop less severe hypertension (8,9). These observations continue to expand the complexity of renovascular injury both in blood vessels and within the kidney itself. Previous studies established activation of the renin–angiotensin system and sympatho–adrenergic axes in more advanced stages of the disease, when vascular occlusion reaches the level of reducing kidney perfusion pressures and blood flow (10). These effector arms themselves are capable of amplifying and differentiating PBMCs into injured endothelium and microvascular segments. Cytokines and chemokines produced by such cells are known to activate profibrotic pathways that lead eventually to loss of functioning kidney parenchyma. Experimental models of 2-kidney-1-clip hypertension in mice are associated with profound stimulation of TGFβ, which is capable of recruiting a variety of inflammatory cells as part of kidney injury (11). Likewise, advanced renal artery occlusion is associated with widespread inflammatory change and fibrosis in humans (12). Our preliminary data indicate that progressive vascular occlusion in humans subjects undergoing transjugular biopsy also is associated with T cell and macrophage infiltration (13), despite blockade of the renin–angiotensin system. At nephrectomy, the degree of fibrotic injury is reduced in patients treated with statins (14). However, such mechanisms likely were not yet activated in the patients included in the study by Kotliar et al. (4), because those patients with renal artery stenoses were in the range traditionally considered to be hemodynamically insignificant. Can the profile of circulating PBMCs provide a marker for incipient vascular disease and/or renal injury? Recent studies implicate many mediators of hypertension, such as reactive oxygen species, vessel stretch, salt intake, and angiotensin, as stimuli for proinflammatory transcription factors, such as NF-κB and activating protein-1 (15). Some of these factors, in turn, activate production of adhesion molecules and chemokines that lead to accumulation of inflammatory cells. Experimental studies targeted at reducing oxidative stress can reduce inflammatory markers (16). Hence, extensive crosstalk seems to occur between classic stimuli for vasoconstriction and vasomotor control mechanisms and known regulators of inflammation within both tissue and circulation. Exactly how this crosstalk can be modified and accelerate disease mechanisms are active areas of current research in many hypertensive disease states. It is important to note that the patterns of inflammatory cell activation observed in this study in patients with renal atherosclerotic disease are generally similar to those patterns observed in subjects with other forms of atherosclerosis or hypertension (17,18). However, although inflammatory infiltration within atherosclerotic lesions seems to promote plaque rupture (19), the composition and phenotype of circulating T lymphocytes do not always reflect those factors in the plaques (17) and are not necessarily a useful indicator of the extent or severity of carotid and coronary atherosclerosis (20). Whether the levels of such cells reflect severity of renal atherosclerotic disease remains to be determined. Future studies are needed to examine patient cohorts with more significant RAD, true renovascular hypertension, and alterations of renal function. Can studies of vessel and/or tissue inflammation provide insight as to the limitations of direct vascular intervention in renovascular disease? A major paradox in our understanding of renal artery stenosis and ischemic nephropathy has been the limited benefit of restoring vascular patency to reverse this disorder (21). It has long been recognized that short duration of renovascular hypertension is among the strongest predictors of clinical benefit from renal revascularization (10). Both observational and prospective clinical trials indicate that revascularization alone only occasionally produces recovery of kidney function. Long-term outcomes in patients with advanced parenchymal injury indicate that substantial numbers of such patients progress to advanced kidney failure and ESRD requiring replacement therapy (22). Tissue samples from such patients show not only glomerular collapse and tubular atrophy but widespread tissue inflammation with abundant infiltration of T cells, macrophages, and dendritic cells (14). Experimental studies using cell-based endothelial progenitor cells indicate that blood flow and function sometimes can be restored, presumably by boosting microvascular repair (23). Inhibition of the monocyte chemoattractant protein in swine renal artery stenosis was associated with reduced renal inflammation and oxidative stress that led to reduction of parenchymal injury (24). Preliminary studies with cell-based immunomodulation associated with intra-arterial infusion of mesenchymal stem cells suggest that inflammatory markers in experimental renovascular disease can be modified with partial restoration of renal function (25). Although it is premature to apply these studies to human disease, identification of prominent inflammatory activation early in atherosclerotic vascular disease, both in the large vessels and within kidney parenchyma, promises to extend our understanding of the pathogenesis and evolution of these disorders. Stay tuned to this program. More to come. Disclosures None. Acknowledgments This work was supported by National Institutes of Health Grants P01HL85307 and DK76308 and National Institutes of Health/National Center for Research Resources Center for Translational Science Activities Grant UL1 RR024150." @default.
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• W2051919705 title "Inflammatory Cell Markers as Indicators of Atherosclerotic Renovascular Disease" @default.
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