Plasma S100A12 Level Is Associated with Cardiovascular Disease in Hemodialysis Patients

Shiotsu, Yayoi; Mori, Yoshihide; Nishimura, Masato; Sakoda, Chikako; Tokoro, Toshiko; Hatta, Tsuguru; Maki, Norio; Iida, Kumiko; Iwamoto, Noriyuki; Ono, Toshihiko; Matsuoka, Eiko; Kishimoto, Noriko; Tamagaki, Keiichi; Matsubara, Hiroaki; Kosaki, Atsushi

doi:10.2215/cjn.08310910

Cited by 56 publications

(56 citation statements)

References 31 publications

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“…However, we did not find a reduction in EN-RAGE levels after calcitriol treatment; in fact, we observed an increase. The sRAGE levels we detected were similar to those in previous reports (Kalousova et al 2006;Nakashima et al 2010), although our EN-RAGE levels were relatively higher than those previously reported (Mori et al 2009;Nakashima et al 2010;Shiotsu et al 2011;Zakiyanov et al 2011). The precise reason for such discrepancy is not clear.…”

Section: Discussionsupporting

confidence: 89%

“…We also hypothesized that SHP status would affect EN-RAGE levels, as the positive relationship between 1,25D and sRAGE and the inverse relationship between sRAGE and EN-RAGE were discovered after calcitriol treatment, although this warrants further investigation. Because the observed increase in sRAGE and reduction in EN-RAGE may be related to CVD, hypertension, and atherosclerosis in patients with ESRD (Mori et al 2009;Nakashima et al 2010;Shiotsu et al 2011;Wu et al 2011;Kim et al 2012), the previously unreported relationship between SHP and EN-RAGE levels merits additional study.…”

Section: Discussionmentioning

confidence: 99%

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Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

Sung

Chung

Kim

et al. 2013

Tohoku J. Exp. Med.

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Cardiovascular disease is common in the patients with end-stage renal disease, who often suffer from secondary hyperparathyroidism (SHP). Vitamin D is considered for the first-line therapy managing SHP in hemodialysis (HD) patients and has a beneficial effect in the chronic inflammation and development of cardiovascular disease. The soluble receptor for advanced glycation end products (sRAGE) may be protective by binding AGE in the pathogenesis of atherosclerotic vascular complications, whereas extracellular RAGE-binding protein (EN-RAGE) represents pro-inflammatory ligands for RAGE. We have hypothesized that vitamin D treatment may alter the levels of sRAGE and EN-RAGE in HD patients. Therefore, this prospective observational study was performed in 51 HD patients with SHP who had low serum 1,25 dihydroxyvitamin D 3 (1,25D) levels and elevated intact parathyroid hormone (PTH) levels. We evaluated the changes in the values of sRAGE, EN-RAGE, and other inflammatory marker, interleukin-6 (IL-6), before and at the end of the 8-week calcitriol treatment. After calcitriol treatment, the serum levels of 1,25D were increased, whereas the serum intact PTH levels were decreased. In addition, the sRAGE levels were increased, whereas those of IL-6 were decreased after calcitriol treatment. A positive correlation between 1,25D and sRAGE levels (r = 0.609, P < 0.001) and a negative correlation between sRAGE and EN-RAGE levels (r = −0.368, P = 0.020) were detected after calcitriol treatment. This study suggests that calcitriol treatment could play an anti-inflammatory role through the increasing sRAGE in HD patients with SHP.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

Sung

Chung

Kim

et al. 2013

Tohoku J. Exp. Med.

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“…27 However, RAGE ligands do accumulate in the context of uremia and are correlated with cardiovascular mortality. 31,40,41 Moreover, Bro et al 27 reported that the administration of anti-RAGE antibodies limited uremia-induced atherosclerois in mice. RAGE promotes the migration of various cell types.…”

Section: Figure 5 Serum Amyloid a (Saa) Induces The Receptor For Advmentioning

confidence: 99%

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Belmokhtar

Robert

Ortillon

et al. 2016

ATVB

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Objective-Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. Approach and Results-We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe −/− background. Sham-operated mice were used as controls. Primary cultures of Ager +/+ and Ager −/− vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe −/− than in sham-operated Apoe −/− mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of α-SMA. Ager transcript levels in the aorta were 6× higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe −/− Ager −/− mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager +/+ but not of Ager −/− VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogenactivated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA. Conclusions-Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager −/− animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE. This manuscript was sent to Ryozo Nagai, Consulting Editor, for review by expert referees, editorial decision, and final disposition. marker of cardiovascular risk. 6 High levels have been reported in uremic patients and are independently associated with cardiovascular mortality.7 SAA has also been reported to play an active role in the atherogenic process. 6,8,9 First, SAA has been detected in the atherosclerotic lesions of hyperlipidem...

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“…36 Levels of S100A12 mRNA in peripheral leukocytes, and protein in serum from chronic kidney disease patients with CVD are elevated 37 and higher in hemodialysis patients with atherosclerosis than in controls, 38 possibly reflecting a systemic inflammatory state. A cross-sectional study 39 suggests S100A12 involvement in the progression of atherosclerosis as a complication of endstage renal disease. S100A12 levels correlate positively with maximum carotid intima-media thickness, 38 prevalence of peripheral arterial disease, carotid atherosclerosis and/or plaque formation, 40 and predict CVD-related mortality.…”

Section: Calgranulins In Diseases Predisposing To Cardiovascular Riskmentioning

confidence: 99%

Calgranulins May Contribute Vascular Protection In Atherogenesis

Geczy

Chung

Hiroshima

2014

Circ J

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Plasma S100A12 Level Is Associated with Cardiovascular Disease in Hemodialysis Patients

Cited by 56 publications

References 31 publications

Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Calgranulins May Contribute Vascular Protection In Atherogenesis

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