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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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Positive immunohistochemical staining of PTX3 in resistance subcutaneous arteries from CKD stage 5 patients.Positive staining (brown) is shown in representative biopsies of CKD-5 patients (A, C) and non-CKD controls (B, D). No immunoreactivity was observed when anti-PTX3 antibody was absent (E). The PTX3-immunoreactivity is abundant in arteries, especially in endothelial cells of tunica intima, indicated by black arrowheads, both in patients (C) and controls (D). The slides were counterstained with hematoxylin. Images are magnified x10 (B), x20 (A, D, E) or x40 (C); scale bar 100 µm.
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pone-0063493-g003: Positive immunohistochemical staining of PTX3 in resistance subcutaneous arteries from CKD stage 5 patients.Positive staining (brown) is shown in representative biopsies of CKD-5 patients (A, C) and non-CKD controls (B, D). No immunoreactivity was observed when anti-PTX3 antibody was absent (E). The PTX3-immunoreactivity is abundant in arteries, especially in endothelial cells of tunica intima, indicated by black arrowheads, both in patients (C) and controls (D). The slides were counterstained with hematoxylin. Images are magnified x10 (B), x20 (A, D, E) or x40 (C); scale bar 100 µm.

Mentions: Circulating asymmetric dimethylarginine (ADMA) and the Arginine/ADMA ratio were used as surrogate biomarkers of endothelial dysfunction. Both plasma PTX3 and SAT PTX3 mRNA levels correlated negatively to Arginine/ADMA ratio, whereas circulating ADMA correlated positively to PTX3 mRNA levels in Spearman rank correlation analyses (Table 2). Moreover, ADMA was identified as a significant predictor of SAT PTX3 mRNA expression, independent of age, sex, DM and plasma PTX3 (Table 3). No associations between plasma PTX3, SAT PTX3 mRNA, ADMA levels AND Arginine/ADMA ratio were observed in the non-CKD group (data not shown). Functional studies on isolated arteries from a subset of CKD-5 patients and non-CKD controls demonstrated a negative correlation (rho = −0.58, p = 0.002) between SAT PTX3 mRNA expression and basal tone after NOS/COX inhibition (Figure 1F) in patients but not in controls. However, there was no correlation between basal tone after NOS and COX inhibition and mRNA expression in fat tissue for other inflammatory markers tested; i.e. IL-6, TNF, CD68 and MCP1 (data not shown). Immunostaining revealed abundant PTX3 immunoreactivity in the vascular wall, possibly with a predominance in endothelial cells, of subcutaneous arteries of CKD-5 patients (Figure 3). However, the PTX3 immunoreactivity intensity in patient arteries did not differ from that of control subjects (2.3 [1.3–3.0] vs. 2.0 [1.0–3.0] a.u., p = 0.13).


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)

Positive immunohistochemical staining of PTX3 in resistance subcutaneous arteries from CKD stage 5 patients.Positive staining (brown) is shown in representative biopsies of CKD-5 patients (A, C) and non-CKD controls (B, D). No immunoreactivity was observed when anti-PTX3 antibody was absent (E). The PTX3-immunoreactivity is abundant in arteries, especially in endothelial cells of tunica intima, indicated by black arrowheads, both in patients (C) and controls (D). The slides were counterstained with hematoxylin. Images are magnified x10 (B), x20 (A, D, E) or x40 (C); scale bar 100 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643920&req=5

pone-0063493-g003: Positive immunohistochemical staining of PTX3 in resistance subcutaneous arteries from CKD stage 5 patients.Positive staining (brown) is shown in representative biopsies of CKD-5 patients (A, C) and non-CKD controls (B, D). No immunoreactivity was observed when anti-PTX3 antibody was absent (E). The PTX3-immunoreactivity is abundant in arteries, especially in endothelial cells of tunica intima, indicated by black arrowheads, both in patients (C) and controls (D). The slides were counterstained with hematoxylin. Images are magnified x10 (B), x20 (A, D, E) or x40 (C); scale bar 100 µm.
Mentions: Circulating asymmetric dimethylarginine (ADMA) and the Arginine/ADMA ratio were used as surrogate biomarkers of endothelial dysfunction. Both plasma PTX3 and SAT PTX3 mRNA levels correlated negatively to Arginine/ADMA ratio, whereas circulating ADMA correlated positively to PTX3 mRNA levels in Spearman rank correlation analyses (Table 2). Moreover, ADMA was identified as a significant predictor of SAT PTX3 mRNA expression, independent of age, sex, DM and plasma PTX3 (Table 3). No associations between plasma PTX3, SAT PTX3 mRNA, ADMA levels AND Arginine/ADMA ratio were observed in the non-CKD group (data not shown). Functional studies on isolated arteries from a subset of CKD-5 patients and non-CKD controls demonstrated a negative correlation (rho = −0.58, p = 0.002) between SAT PTX3 mRNA expression and basal tone after NOS/COX inhibition (Figure 1F) in patients but not in controls. However, there was no correlation between basal tone after NOS and COX inhibition and mRNA expression in fat tissue for other inflammatory markers tested; i.e. IL-6, TNF, CD68 and MCP1 (data not shown). Immunostaining revealed abundant PTX3 immunoreactivity in the vascular wall, possibly with a predominance in endothelial cells, of subcutaneous arteries of CKD-5 patients (Figure 3). However, the PTX3 immunoreactivity intensity in patient arteries did not differ from that of control subjects (2.3 [1.3–3.0] vs. 2.0 [1.0–3.0] a.u., p = 0.13).

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