Aberrant Activation of the TNF‐α System and Production of Fas and Scavenger Receptors on Monocytes in Patients With End‐stage Renal Disease

Wu, Chia Chao; Chen, Jin Shuen; Lin, Shih Hua; Chu, Pauling; Lin, Yuh Feng; Lin, Su M.; Liao, Tung Nan

doi:10.1111/j.1525-1594.2005.29110.x

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…Interestingly, numerous studies have suggested enhanced scavenger receptor expression on cells of the monocyte/macrophage lineage, along with defects in macrophage cholesterol efflux, in humans with CKD. [29][30][31][32][33] Furthermore, studies in ApoE 2/2 mice, a rodent model of atherosclerosis, demonstrate that induction of kidney disease in this model enhances macrophage cholesterol accumulation independent of alterations in plasma cholesterol concentrations. 34 This investigation has both important strengths and limitations.…”

Section: Discussionmentioning

confidence: 99%

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Stubbs

House

Ocque

et al. 2016

Journal of the American Society of Nephrology

342

328

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Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r 2 =0.31, P,0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 mM [54.8-133.0 mM] for dialysis-dependent patients versus 3.3 mM [3.1-6.0 mM] for healthy controls; P,0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 mM [29.2-189.7 mM] pretransplant versus 11.4 mM [8.9-20.2 mM] posttransplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 mM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P,0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography. Patients with CKD have a high prevalence of cardiovascular comorbidities, which primarily contributes to the exceedingly high mortality in this group. 1,2 For example, the 5-year survival for ESRD patients receiving dialysis is approximately 35%, with .50% of the mortality in this group resulting directly from cardiovascular causes. 1 It is well established that CKD patients exhibit a disproportionate burden of atherosclerosis as compared with individuals having normal kidney function. [2][3][4][5] Furthermore, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as hypertension, diabetes and hyperlipidemia, only partially accounts for the accelerated atherosclerosis in CKD patients, leading to the hypothesis that unique risk factors must be present in this population. 6,7

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Section: Discussionmentioning

confidence: 99%

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Stubbs

House

Ocque

et al. 2016

Journal of the American Society of Nephrology

342

328

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“…Apoptosis is initiated by a variety of stimuli, including DNA damage, toxins, oxidant stress, and cytokines (especially TNF- α ) [110]. Galli et al have shown that the apoptotic rate is increased in chronic HD patients and that this increase is associated with oxidative stress [111].…”

Section: Consequences Of Oxidative Stress and Oxidative Nucleic Acmentioning

confidence: 99%

“…Apoptosis can be initiated by death-signal-inducing receptors, of which Fas (CD95) is the best known. In our previous study, we reported increased immunofluorescence of the apoptosis marker for Fas, CD95, in monocytes from uremic patients [110]. …”

Section: Consequences Of Oxidative Stress and Oxidative Nucleic Acmentioning

confidence: 99%

Oxidative Stress and Nucleic Acid Oxidation in Patients with Chronic Kidney Disease

Sung

Hsu

Chen

et al. 2013

Oxidative Medicine and Cellular Longevity

Self Cite

154

110

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Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity and a high risk for developing malignancy. Excessive oxidative stress is thought to play a major role in elevating these risks by increasing oxidative nucleic acid damage. Oxidative stress results from an imbalance between reactive oxygen/nitrogen species (RONS) production and antioxidant defense mechanisms and can cause vascular and tissue injuries as well as nucleic acid damage in CKD patients. The increased production of RONS, impaired nonenzymatic or enzymatic antioxidant defense mechanisms, and other risk factors including gene polymorphisms, uremic toxins (indoxyl sulfate), deficiency of arylesterase/paraoxonase, hyperhomocysteinemia, dialysis-associated membrane bioincompatibility, and endotoxin in patients with CKD can inhibit normal cell function by damaging cell lipids, arachidonic acid derivatives, carbohydrates, proteins, amino acids, and nucleic acids. Several clinical biomarkers and techniques have been used to detect the antioxidant status and oxidative stress/oxidative nucleic acid damage associated with long-term complications such as inflammation, atherosclerosis, amyloidosis, and malignancy in CKD patients. Antioxidant therapies have been studied to reduce the oxidative stress and nucleic acid oxidation in patients with CKD, including alpha-tocopherol, N-acetylcysteine, ascorbic acid, glutathione, folic acid, bardoxolone methyl, angiotensin-converting enzyme inhibitor, and providing better dialysis strategies. This paper provides an overview of radical production, antioxidant defence, pathogenesis and biomarkers of oxidative stress in patients with CKD, and possible antioxidant therapies.

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“…scavenger receptors are upregulated in macro phages from patients with CKD as well as in tissues such as the aorta and kidneys of animals with renal injury. 77,78,83–86 monocytes from patients on hemo-dialysis or peritoneal dialysis have higher levels of CD36 than monocytes from patients with CKD who are not on dialysis or individuals without renal disease. 77,78 increased expression of SR-A has also been documented in macro phages from patients on hemodialysis.…”

Section: Ckd and Macrophage Lipid Homeostasismentioning

confidence: 96%

“…77,78 one study showed that CD36-mediated uptake of oxidized LDL induced actin polymerization and cell spreading via activation of focal adhesion kinase and inactivation of src homology 2-containing phosphotyrosine phosphatase, which inhibited cellular migration. 79 other investigators, however, have reported that upregulation of CD36 actually enhances macrophage migration.…”

Section: Ckd Modulates Macrophage Functionmentioning

confidence: 99%

Atherosclerosis in chronic kidney disease: the role of macrophages

2010

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Patients with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease and loss of renal parenchyma accelerates atherosclerosis in animal models. Macrophages are central to atherogenesis because they regulate cholesterol traffic and inflammation in the arterial wall. CKD influences macrophage behavior at multiple levels, rendering them proatherogenic. Even at normal creatinine levels, macrophages from uninephrectomized Apoe−/− mice are enriched in cholesterol owing to downregulation of cholesterol transporter ATP-binding cassette subfamily A member 1 levels and activation of nuclear factor κB, which leads to impaired cholesterol efflux. Interestingly, treatment with an angiotensin-II-receptor blocker (ARB) improves these effects. Moreover, atherosclerotic aortas from Apoe−/− mice transplanted into renal-ablated normocholesterolemic recipients show plaque progression and increased macrophage content instead of the substantial regression seen in recipient mice with intact kidneys. ARBs reduce atherosclerosis development in mice with partial renal ablation. These results, combined with the clinical benefits of angiotensin-converting-enzyme (ACE) inhibitors and ARBs in patients with CKD, suggest an important role for the angiotensin system in the enhanced susceptibility to atherosclerosis seen across the spectrum of CKD. The role of macrophages could explain why these therapies may be effective in end-stage renal disease, one of the few conditions in which statins show no clinical benefit.

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Aberrant Activation of the TNF‐α System and Production of Fas and Scavenger Receptors on Monocytes in Patients With End‐stage Renal Disease

Cited by 12 publications

References 24 publications

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Oxidative Stress and Nucleic Acid Oxidation in Patients with Chronic Kidney Disease

Atherosclerosis in chronic kidney disease: the role of macrophages

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