Elevated Circulating Levels and Tissue Expression of Pentraxin 3 in Uremia: A Reflection of Endothelial Dysfunction

Elevated systemic pentraxin 3 (PTX3) levels appear to be a powerful marker of inflammatory status and a superior outcome predictor in patients with chronic kidney disease (CKD). As previous data imply that PTX3 is involved in vascular pathology and that adipose tissue mass may influence circulating PTX3 levels, we aimed to study the importance of adipose tissue expression of PTX3 in the uremic milieu and its relation to endothelial dysfunction parameters. Plasma PTX3 and abdominal subcutaneous adipose tissue (SAT) PTX3 mRNA levels were quantified in 56 stage 5 CKD patients (median age 57 [range 25–75] years, 30 males) and 40 age and gender matched controls (median age 58 [range 20–79] years, 27 males). Associations between PTX3 measures and an extensive panel of clinical parameters, including surrogate markers of endothelial function, were assessed. Functional ex vivo studies on endothelial status and immunohistochemical staining for PTX3 were conducted in resistance subcutaneous arteries isolated from SAT. SAT PTX3 mRNA expression correlated with plasma PTX3 concentrations (rho = 0.54, p = 0.0001) and was increased (3.7 [0.4–70.3] vs. 1.2 [0.2–49.3] RQ, p = 0.02) in CKD patients with cardiovascular disease (CVD), but was not significantly different between patients and controls. The association to CVD was lost after adjustments. SAT PTX3 mRNA levels were independently correlated to asymmetric dimethylarginine and basal resistance artery tone developed after inhibition with nitric oxide synthase and cyclooxygenase (rho = −0.58, p = 0.002). Apparent positive PTX3 immunoreactivity was observed in both patient and control arteries. In conclusion, fat PTX3 mRNA levels are associated with measures of endothelial cell function in patients with CKD. PTX3 may be involved in adipose tissue-orchestrated mechanisms that are restricted to the uremic milieu and modify inflammation and vascular complications in CKD patients.

[1]  C. Garlanda,et al.  PTX3 as a potential endothelial dysfunction biomarker for severity of preeclampsia and IUGR. , 2012, Placenta.

[2]  A. Sonmez,et al.  High plasma level of long Pentraxin 3 is associated with insulin resistance in women with polycystic ovary syndrome , 2012, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[3]  J. Carrero,et al.  Mechanisms of Endothelial Dysfunction in Resistance Arteries from Patients with End-Stage Renal Disease , 2012, PloS one.

[4]  J. Carrero,et al.  Prolactin levels, endothelial dysfunction, and the risk of cardiovascular events and mortality in patients with CKD. , 2012, Clinical journal of the American Society of Nephrology : CJASN.

[5]  W. Ryu,et al.  Pentraxin 3: a novel and independent prognostic marker in ischemic stroke. , 2012, Atherosclerosis.

[6]  M. Shlipak,et al.  Associations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: data from the Heart and Soul Study. , 2012, American heart journal.

[7]  P. Cieślik,et al.  Long pentraxin 3 (PTX3) in the light of its structure, mechanism of action and clinical implications , 2012, Autoimmunity.

[8]  T. Morishita,et al.  Number of endothelial progenitor cells in peripheral artery disease as a marker of severity and association with pentraxin-3, malondialdehyde-modified low-density lipoprotein and membrane type-1 matrix metalloproteinase. , 2012, Journal of atherosclerosis and thrombosis.

[9]  J. Moreno-Navarrete,et al.  Plasma PTX3 protein levels inversely correlate with insulin secretion and obesity, whereas visceral adipose tissue PTX3 gene expression is increased in obesity. , 2011, American journal of physiology. Endocrinology and metabolism.

[10]  J. Carrero,et al.  Inverse relationship between the inflammatory marker pentraxin-3, fat body mass, and abdominal obesity in end-stage renal disease. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[11]  N. Kume,et al.  Pentraxin 3 as a biomarker for acute coronary syndrome: comparison with biomarkers for cardiac damage. , 2011, Journal of cardiology.

[12]  J. Carrero,et al.  Impaired resistance artery function in patients with end-stage renal disease. , 2011, Clinical science.

[13]  J. Carrero,et al.  Increased expression of pro‐inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients , 2011, Journal of internal medicine.

[14]  J. Carrero,et al.  Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[15]  C. Garlanda,et al.  Pentraxins and atherosclerosis: the role of PTX3. , 2011, Current pharmaceutical design.

[16]  P. Stenvinkel,et al.  Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease , 2010, Journal of internal medicine.

[17]  T. Kodama,et al.  Reciprocal Contribution of Pentraxin 3 and C‐Reactive Protein to Obesity and Metabolic Syndrome , 2010, Obesity.

[18]  P. Stenvinkel,et al.  Inflammation in End‐Stage Renal Disease—What Have We Learned in 10 Years? , 2010, Seminars in dialysis.

[19]  M. Haluzík,et al.  Increased proinflammatory cytokine production in adipose tissue of obese patients with chronic kidney disease , 2010, Wiener klinische Wochenschrift.

[20]  H. Sasai,et al.  Is pentraxin 3 involved in obesity-induced decrease in arterial distensibility? , 2010, Journal of atherosclerosis and thrombosis.

[21]  J. Carrero,et al.  Abdominal fat deposition is associated with increased inflammation, protein-energy wasting and worse outcome in patients undergoing haemodialysis. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[22]  C. Garlanda,et al.  Deficiency of the Long Pentraxin PTX3 Promotes Vascular Inflammation and Atherosclerosis , 2009, Circulation.

[23]  H. Staines,et al.  The long pentraxin 3 (PTX3): a novel prognostic inflammatory marker for mortality in acute chest pain , 2009, Thrombosis and Haemostasis.

[24]  T. Roubíček,et al.  Increased production of proinflammatory cytokines in adipose tissue of patients with end-stage renal disease. , 2009, Nutrition.

[25]  J. Carrero,et al.  Effect of renin angiotensin system blockade on pentraxin 3 levels in type-2 diabetic patients with proteinuria. , 2009, Clinical journal of the American Society of Nephrology : CJASN.

[26]  A. Mantovani,et al.  Expression of long pentraxin PTX3 in human adipose tissue and its relation with cardiovascular risk factors. , 2009, Atherosclerosis.

[27]  C. Garlanda,et al.  Pentraxins, humoral innate immunity and tissue injury. , 2008, Current opinion in immunology.

[28]  J. Carrero,et al.  Novel links between the long pentraxin 3, endothelial dysfunction, and albuminuria in early and advanced chronic kidney disease. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[29]  J. Axelsson,et al.  Waist circumference and visceral fat in CKD: a cross-sectional study. , 2008, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[30]  P. Arner,et al.  Expression of six transmembrane protein of prostate 2 in human adipose tissue associates with adiposity and insulin resistance. , 2008, The Journal of clinical endocrinology and metabolism.

[31]  J. Carrero,et al.  The long pentraxin PTX-3 in prevalent hemodialysis patients: associations with comorbidities and mortality. , 2008, QJM : monthly journal of the Association of Physicians.

[32]  T. Ikizler,et al.  Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. , 2008, Journal of the American Society of Nephrology : JASN.

[33]  Peter Stenvinkel,et al.  Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle? , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[34]  C. Garlanda,et al.  Cardioprotective Function of the Long Pentraxin PTX3 in Acute Myocardial Infarction , 2008, Circulation.

[35]  K. Hultenby,et al.  Endothelium-derived hyperpolarizing factor in preeclampsia: heterogeneous contribution, mechanisms, and morphological prerequisites. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[36]  J. Carrero,et al.  Plasma pentraxin 3 in patients with chronic kidney disease: associations with renal function, protein-energy wasting, cardiovascular disease, and mortality. , 2007, Clinical journal of the American Society of Nephrology : CJASN.

[37]  R. Schindler,et al.  Pentraxin 3 is elevated in haemodialysis patients and is associated with cardiovascular disease. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[38]  C. Garlanda,et al.  The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps , 2007, The Journal of experimental medicine.

[39]  J. Carrero,et al.  Changes in fat mass correlate with changes in soluble sCD163, a marker of mature macrophages, in patients with CKD. , 2006, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[40]  Paul M Ridker,et al.  C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. , 2006, Journal of the American College of Cardiology.

[41]  C. Kallenberg,et al.  Abundance of the long pentraxin PTX3 at sites of leukocytoclastic lesions in patients with small-vessel vasculitis. , 2006, Arthritis and rheumatism.

[42]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[43]  C. Garlanda,et al.  Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. , 2005, Annual review of immunology.

[44]  P. Stenvinkel,et al.  Truncal fat mass as a contributor to inflammation in end-stage renal disease. , 2004, The American journal of clinical nutrition.

[45]  Gianni Tognoni,et al.  Prognostic Significance of the Long Pentraxin PTX3 in Acute Myocardial Infarction , 2004, Circulation.

[46]  A. Cheung,et al.  Association of obesity with inflammation in chronic kidney disease: a cross-sectional study. , 2004, Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation.

[47]  A. Mantovani,et al.  Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells. , 2004, Atherosclerosis.

[48]  Alberto Mantovani,et al.  Production of the soluble pattern recognition receptor PTX3 by myeloid, but not plasmacytoid, dendritic cells , 2003, European journal of immunology.

[49]  A. Mantovani,et al.  The Long Pentraxin Ptx3 Is Synthesized in IgA Glomerulonephritis and Activates Mesangial Cells 1 , 2003, The Journal of Immunology.

[50]  C. Garlanda,et al.  Production of the Long Pentraxin PTX3 in Advanced Atherosclerotic Plaques , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[51]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[52]  P. Stenvinkel.  Endothelial dysfunction and inflammation-is there a link? , 2001, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[53]  A. Mantovani,et al.  Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA) , 2000, Clinical and experimental immunology.

[54]  P. Groot,et al.  Chemokines and atherosclerosis. , 1999, Atherosclerosis.

[55]  P. Stenvinkel,et al.  Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. , 1999, Kidney international.

[56]  D. Moczulski,et al.  Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. , 1998, Diabetes.

[57]  R. Hanson,et al.  Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. , 1998, Diabetes.

[58]  A. Mantovani,et al.  Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes. , 1994, Blood.

[59]  J. Vilček,et al.  TSG-14, a tumor necrosis factor- and IL-1-inducible protein, is a novel member of the pentaxin family of acute phase proteins. , 1993, Journal of immunology.

[60]  M. Rocchi,et al.  Interleukin-1-inducible genes in endothelial cells. Cloning of a new gene related to C-reactive protein and serum amyloid P component. , 1992, The Journal of biological chemistry.