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Elevated circulating levels and tissue expression of pentraxin 3 in uremia: a reflection of endothelial dysfunction.

Witasp A, Rydén M, Carrero JJ, Qureshi AR, Nordfors L, Näslund E, Hammarqvist F, Arefin S, Kublickiene K, Stenvinkel P - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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.

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PTX3 mRNA is expressed in isolated adipocytes and levels correlate with endothelial dysfunction in CKD patients.(A) Plasma PTX3 concentrations (ng/ml) measured in 39 non-CKD controls and 53 patients with CKD stage 5. PTX3 mRNA quantities (relative quantity, RQ, arbitrary units) analysed in (B) abdominal subcutaneous adipose tissue of 40 non-CKD controls and 56 patients with CKD stage 5, (C) subcutaneous and visceral fat depots obtained from 20 non-CKD patients, (D) isolated adipocytes and intact adipose tissue (n = 14) as well as in (E) patients with CKD stage 5 and no diabetes mellitus (n = 35), diabetes mellitus type 1 (n = 8) or diabetes mellitus type 2 (n = 13). (F) Negative correlation (Spearman's rank) between subcutaneous adipose tissue PTX3 mRNA quantities (log transformed) and constriction (basal tone) after nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition in 27 patients with CKD stage 5. Statistical differences between groups were evaluated with Wilcoxon rank sum test (A–B), Wilcoxon signed rank test (C–D) and Kruskal-Wallis one-way analysis of variance (E). **, p<0.01; ***, p<0.001; ****, p<0.0001.
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pone-0063493-g001: PTX3 mRNA is expressed in isolated adipocytes and levels correlate with endothelial dysfunction in CKD patients.(A) Plasma PTX3 concentrations (ng/ml) measured in 39 non-CKD controls and 53 patients with CKD stage 5. PTX3 mRNA quantities (relative quantity, RQ, arbitrary units) analysed in (B) abdominal subcutaneous adipose tissue of 40 non-CKD controls and 56 patients with CKD stage 5, (C) subcutaneous and visceral fat depots obtained from 20 non-CKD patients, (D) isolated adipocytes and intact adipose tissue (n = 14) as well as in (E) patients with CKD stage 5 and no diabetes mellitus (n = 35), diabetes mellitus type 1 (n = 8) or diabetes mellitus type 2 (n = 13). (F) Negative correlation (Spearman's rank) between subcutaneous adipose tissue PTX3 mRNA quantities (log transformed) and constriction (basal tone) after nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition in 27 patients with CKD stage 5. Statistical differences between groups were evaluated with Wilcoxon rank sum test (A–B), Wilcoxon signed rank test (C–D) and Kruskal-Wallis one-way analysis of variance (E). **, p<0.01; ***, p<0.001; ****, p<0.0001.

Mentions: Median plasma PTX3 protein level was significantly higher in patients than in controls (1.4 [0.4–7.5] vs. 0.7 [0.1–2.2] ng/ml, p<0.0001, Figure 1A). PTX3 mRNA was expressed in both patient and control SAT but no significant differences were observed (1.9 [0.2–70.3] vs. 1.0 [0.3–30.1] RQ, p = 0.16, Figure 1B). Univariate analyses showed that plasma PTX3 and PTX3 mRNA expression were positively correlated in patients (Table 2), but not in the non-CKD controls (data not shown). In a multivariate model, plasma PTX3 was a significant predictor of PTX3 mRNA independent of age, sex and diabetes (Table 3). Circulating IL-6 concentrations, but not TNF and CRP, were positively correlated to plasma PTX3 (Table 2). Uremic patients with a medical history of CVD had a significantly higher circulating median PTX3 (1.8 [0.5–7.5] vs. 1.1 [0.4–5.9] ng/ml, p = 0.02) and SAT PTX3 mRNA levels (3.7 [0.4–70.0] vs. 1.2 [0.2–49.3] RQ, p = 0.02) compared to patients without CVD events. When adjusting for predictors of CVD (age, sex, diabetes mellitus) as well as ADMA levels and Arginine/ADMA ratio in multivariate logistic regression models this association was lost (Table 4).


Elevated circulating levels and tissue expression of pentraxin 3 in uremia: a reflection of endothelial dysfunction.

Witasp A, Rydén M, Carrero JJ, Qureshi AR, Nordfors L, Näslund E, Hammarqvist F, Arefin S, Kublickiene K, Stenvinkel P - PLoS ONE (2013)

PTX3 mRNA is expressed in isolated adipocytes and levels correlate with endothelial dysfunction in CKD patients.(A) Plasma PTX3 concentrations (ng/ml) measured in 39 non-CKD controls and 53 patients with CKD stage 5. PTX3 mRNA quantities (relative quantity, RQ, arbitrary units) analysed in (B) abdominal subcutaneous adipose tissue of 40 non-CKD controls and 56 patients with CKD stage 5, (C) subcutaneous and visceral fat depots obtained from 20 non-CKD patients, (D) isolated adipocytes and intact adipose tissue (n = 14) as well as in (E) patients with CKD stage 5 and no diabetes mellitus (n = 35), diabetes mellitus type 1 (n = 8) or diabetes mellitus type 2 (n = 13). (F) Negative correlation (Spearman's rank) between subcutaneous adipose tissue PTX3 mRNA quantities (log transformed) and constriction (basal tone) after nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition in 27 patients with CKD stage 5. Statistical differences between groups were evaluated with Wilcoxon rank sum test (A–B), Wilcoxon signed rank test (C–D) and Kruskal-Wallis one-way analysis of variance (E). **, p<0.01; ***, p<0.001; ****, p<0.0001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3643920&req=5

pone-0063493-g001: PTX3 mRNA is expressed in isolated adipocytes and levels correlate with endothelial dysfunction in CKD patients.(A) Plasma PTX3 concentrations (ng/ml) measured in 39 non-CKD controls and 53 patients with CKD stage 5. PTX3 mRNA quantities (relative quantity, RQ, arbitrary units) analysed in (B) abdominal subcutaneous adipose tissue of 40 non-CKD controls and 56 patients with CKD stage 5, (C) subcutaneous and visceral fat depots obtained from 20 non-CKD patients, (D) isolated adipocytes and intact adipose tissue (n = 14) as well as in (E) patients with CKD stage 5 and no diabetes mellitus (n = 35), diabetes mellitus type 1 (n = 8) or diabetes mellitus type 2 (n = 13). (F) Negative correlation (Spearman's rank) between subcutaneous adipose tissue PTX3 mRNA quantities (log transformed) and constriction (basal tone) after nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition in 27 patients with CKD stage 5. Statistical differences between groups were evaluated with Wilcoxon rank sum test (A–B), Wilcoxon signed rank test (C–D) and Kruskal-Wallis one-way analysis of variance (E). **, p<0.01; ***, p<0.001; ****, p<0.0001.
Mentions: Median plasma PTX3 protein level was significantly higher in patients than in controls (1.4 [0.4–7.5] vs. 0.7 [0.1–2.2] ng/ml, p<0.0001, Figure 1A). PTX3 mRNA was expressed in both patient and control SAT but no significant differences were observed (1.9 [0.2–70.3] vs. 1.0 [0.3–30.1] RQ, p = 0.16, Figure 1B). Univariate analyses showed that plasma PTX3 and PTX3 mRNA expression were positively correlated in patients (Table 2), but not in the non-CKD controls (data not shown). In a multivariate model, plasma PTX3 was a significant predictor of PTX3 mRNA independent of age, sex and diabetes (Table 3). Circulating IL-6 concentrations, but not TNF and CRP, were positively correlated to plasma PTX3 (Table 2). Uremic patients with a medical history of CVD had a significantly higher circulating median PTX3 (1.8 [0.5–7.5] vs. 1.1 [0.4–5.9] ng/ml, p = 0.02) and SAT PTX3 mRNA levels (3.7 [0.4–70.0] vs. 1.2 [0.2–49.3] RQ, p = 0.02) compared to patients without CVD events. When adjusting for predictors of CVD (age, sex, diabetes mellitus) as well as ADMA levels and Arginine/ADMA ratio in multivariate logistic regression models this association was lost (Table 4).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus