Oxidized LDL-anti-oxidized LDL immune complexes and diabetic nephropathy

Atchley, D H; Lopes‐Virella, Maria F.; Zheng, Deyi; Kenny, David J.; Virella, Gabriel

doi:10.1007/s00125-002-0962-y

Cited by 61 publications

(11 citation statements)

References 66 publications

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“…Despite the lower values of LDL-c and the similar values of Ox-LDL in HD patients, the Ox-LDL/LDL-c ratio was significantly higher, suggesting a higher proportion of oxidized LDL particles and, therefore, a lower antioxidant protection within LDL that might be due to the significantly lower activity of PON1. The trend towards lower levels of oxLDL observed in HD patients might result from the formation of immune complexes formed by oxidized LDL and Ox-LDL antibodies, as suggested by some authors [13,14]; proatherogenic and proinflammatory properties have been attributed to these immune complexes and their formation seems to be more prevalent in diabetic nephropathy [13]; considering the high percentage of diabetic patients (36.1%) in our studied patients, this could be a reasonable explanation for the values of Ox-LDL that we observed.…”

Section: Discussionmentioning

confidence: 69%

Main Determinants of PON1 Activity in Hemodialysis Patients

Ribeiro

Faria²,

Mascarenhas-Melo

et al. 2012

Am J Nephrol

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Background/Aims: Cardiovascular diseases are the major cause of morbidity and mortality in hemodialysis (HD) patients. These patients present reduced paraoxonase 1 (PON1) activity that depends on genetic and non-genetic factors; however, how these factors influence PON1 activity in HD patients is poorly clarified. Our aim was to evaluate the influence of two polymorphisms and non-genetic factors on PON1 activity in HD patients. Methods: We evaluated 183 HD patients under recombinant human erythropoietin (rhEPO) treatment and 22 healthy individuals. The lipid profile [total cholesterol, triglycerides, HDL-c, LDL-c, apolipoprotein (Apo) A-I, Apo B, lipoprotein(a) and oxidized low-density lipoprotein (Ox-LDL)], inflammatory markers [adiponectin, interleukin-6 (IL-6) and C-reactive protein (CRP)], PON1 activity and PON1 gene polymorphisms (L55M and Q192R) were evaluated. Results: HD patients presented higher levels of IL-6, CRP and Ox-LDL/LDL-c, and lower PON1 activity, total cholesterol, HDL-c, LDL-c, Apo A and Apo B; the most frequent genotype was heterozygosity for L55M polymorphism and homozygosity for the Q allele, the more frequent genotype of Q192R polymorphism. Multiple regression analysis identified heterozygosity and homozygosity for L55M and Q192R polymorphisms, very low-density lipoproteins, LDL-c, Apo A and CRP levels, time on dialysis and rhEPO dose, as the independent variables significantly associated with PON1 activity. The associations with CRP, rhEPO and time on dialysis were negative. Conclusion: Our results show that the reduced PON1 activity in HD patients who are not under statin therapy is strongly associated with inflammation, longer time on dialysis and high rhEPO doses, suggesting that the reduction in PON1 activity may worsen the prognosis of these patients.

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Section: Discussionmentioning

confidence: 69%

Main Determinants of PON1 Activity in Hemodialysis Patients

Ribeiro

Faria²,

Mascarenhas-Melo

et al. 2012

Am J Nephrol

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“…Previous studies by our group have shown that plasma concentrations of oxLDL-IC were significantly increased in diabetic patients with macroalbuminuria as compared to those with normal albuminuria [35; 36], indicating a positive correlation between oxLDL-ICs and diabetic nephropathy. Diabetic nephropathy is characterized by mesangial expansion with a strong inflammatory component.…”

Section: Discussionmentioning

confidence: 83%

Oxidized LDL immune complexes stimulate collagen IV production in mesangial cells via Fc gamma receptors I and III

Abdelsamie

Huang

et al. 2011

Clinical Immunology

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Diabetic nephropathy is characterized by progressive mesangial expansion. Although we have reported that circulating oxidized LDL-containing immune complexes (oxLDL-ICs) are associated with abnormal levels of albuminuria, the underlying mechanisms have not been investigated. In this study, we have studied the effect of oxLDL-ICs on collagen IV expression by mesangial cells. We found that oxLDL-ICs markedly stimulated collagen IV expression in a concentration- and time-dependent fashion while oxLDL only had moderate effect. We also found that oxLDL-ICs stimulated collagen IV expression by engaging Fc gamma receptor (FcγR) I and III, but not FcγRII, and that p38 MAPK, JNK and PKC pathways were involved in collagen IV expression. Furthermore, we found that oxLDL-ICs stimulated FcγRI expression, suggesting a positive feedback mechanism involved in oxLDL-IC-stimulated collagen IV expression. Taken together, this study showed that oxLDL-ICs stimulated collagen IV in mesangial cells via FcγRI and FcγRIII, and the expression of FcγRI was increased by oxLDL-ICs.

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“…Also in nephropathy, predominance of IgG antibodies (particularly those with higher avidity) over IgM antibodies in oxLDL-IC was associated with parameters indicative of deteriorating renal function in same cohort (Atchley et al, 2002; Virella et al, 2008). Using coronary artery calcification (CAC) indices and carotid IMT as end-points indicative of cardiovascular disease progression we also found that increased levels of oxLDL and of AGE-LDL in circulating IC are associated in the DCCT/EDIC cohort with the development of coronary calcification and with increased levels and progression of carotid IMT.…”

Section: Modified Ldl Concentrations As Risk Factors For Diabetic Commentioning

confidence: 88%

“…Our group has studied extensively the pathogenic role of modified LDL antibodies (Virella et al, 2002, 2008; Saad et al, 2006; Lopes-Virella et al, 2007, 2011a; Lopes-Virella and Virella, 2010), and has developed methodology for the measurement of circulating antibodies to mLDL (Virella et al, 1993) and for the measurement of modified form of LDL and the corresponding antibodies involved in IC formation through the isolation and fractionation of circulating IC (Atchley et al, 2002; Virella et al, 2004, 2005, 2008). Several groups reported studies concerning the possible association between modified LDL (particularly oxLDL) or the corresponding antibodies with cardiovascular disease with conflicting results (Virella and Lopes-Virella, 2003; Lopes-Virella and Virella, 2010).…”

Section: Modified Ldl Concentrations As Risk Factors For Diabetic Commentioning

confidence: 99%

The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes

Virella¹,

Lopes‐Virella²

2012

Front. Endocrin.

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The main causes of morbidity and mortality in diabetes are macro and microvascular complications, including atherosclerosis, nephropathy, and retinopathy. As the definition of atherosclerosis as a chronic inflammatory disease became widely accepted, it became important to define the triggers of vascular inflammation. Oxidative and other modifications of lipids and lipoproteins emerged as major pathogenic factors in atherosclerosis. Modified forms of LDL (mLDL) are pro-inflammatory by themselves, but, in addition, mLDLs including oxidized, malondialdehyde (MDA)-modified, and advanced glycation end (AGE)-product-modified LDL induce autoimmune responses in humans. The autoimmune response involves T cells in the arterial wall and synthesis of IgG antibodies. The IgG auto-antibodies that react with mLDLs generate immune complexes (IC) both intra and extravascularly, and those IC activate the complement system as well as phagocytic cells via the ligation of Fcγ receptors. In vitro studies proved that the pro-inflammatory activity of IC containing mLDL (mLDL-IC) is several-fold higher than that of the modified LDL molecules. Clinical studies support the pathogenic role of mLDL-IC in the development of macrovascular disease patients with diabetes. In type 1 diabetes, high levels of oxidized and AGE-LDL in IC were associated with internal carotid intima-media thickening and coronary calcification. In type 2 diabetes, high levels of MDA-LDL in IC predicted the occurrence of myocardial infarction. There is also evidence that mLDL-IC are involved in the pathogenesis of diabetic nephropathy and retinopathy. The pathogenic role of mLDL-IC is not unique to diabetic patients, because those IC are also detected in non-diabetic individuals. But mLDL-IC are likely to reach higher concentrations and have a more prominent pathogenic role in diabetes due to increased antigenic load secondary to high oxidative stress and to enhanced autoimmune responses in type 1 diabetes.

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Oxidized LDL-anti-oxidized LDL immune complexes and diabetic nephropathy

Cited by 61 publications

References 66 publications

Main Determinants of PON1 Activity in Hemodialysis Patients

Main Determinants of PON1 Activity in Hemodialysis Patients

Oxidized LDL immune complexes stimulate collagen IV production in mesangial cells via Fc gamma receptors I and III

The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes

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