Advanced Glycation End-products Enhance Calcification in Vascular Smooth Muscle Cells

Ren, Xiaomei; Shao, Hongxiang; Qin, Wei; Sun, Zilin; Liu, N

doi:10.1177/147323000903700329

Cited by 59 publications

(50 citation statements)

References 15 publications

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“…4). Expression of RAGE was examined by immunohistochemistry, because the AGE-RAGE axis has been shown to play an important role in vascular calcification in type 2 diabetes [10,11,12,13]. As shown in figure 3, RAGE expression was increased in the aorta of hyperglycemic, uremic/hyperglycemic and uremic rats, but not in the aorta of control rats.…”

Section: Resultsmentioning

confidence: 99%

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High Glucose Concentration Does Not Modulate the Formation of Arterial Medial Calcification in Experimental Uremic Rats

Yoshida

Yamashita²,

Horimai³

et al. 2013

J Vasc Res

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High phosphate-induced phenotypic switching of smooth muscle cells (SMCs) into osteogenic cells is critical for the formation of arterial medial calcification in chronic kidney disease. Because vascular calcification is also prevalent in type 2 diabetes, we examined whether glucose concentration affects high phosphate-induced SMC phenotypic switching and calcification. First, the formation of arterial medial calcification was compared among 4 groups: adenine-fed uremic rats, streptozotocin-injected hyperglycemic rats, adenine-fed and streptozotocin-injected uremic/hyperglycemic rats, and control rats. Calcification was obvious in uremic and uremic/hyperglycemic rats, whereas it was undetectable in the others. Aortic calcium contents were significantly elevated in uremic and uremic/hyperglycemic rats, but they were not different between the two groups. Moreover, hyperglycemia had no effects on the reduced expression of SMC differentiation markers including smooth muscle α-actin and SM22α and on the increased expression of osteogenic markers, such as Runx2, in uremic rats. Second, cultured SMCs were incubated in the medium with various concentrations of phosphate (0.9-4.5 mmol/l) and glucose (5-50 mmol/l), and calcium deposition was measured. Although high phosphate dose-dependently increased calcium contents, they were unaffected by glucose concentration. Results suggest that glucose concentration does not directly modulate high phosphate-induced SMC phenotypic switching and arterial medial calcification.

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Section: Resultsmentioning

confidence: 99%

“…In cultured vascular SMCs, AGEs induced expression of osteopontin, Runx2 and alkaline phosphatase as well as calcium deposition [10,11]. These AGE-mediated changes were partially attenuated by a neutralizing antibody to the receptor for AGE (RAGE).…”

Section: Introductionmentioning

confidence: 99%

High Glucose Concentration Does Not Modulate the Formation of Arterial Medial Calcification in Experimental Uremic Rats

Yoshida

Yamashita²,

Horimai³

et al. 2013

J Vasc Res

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“…RAGE not only promotes atherosclerosis and diabetic cardiovascular and renal complications [17,18,19,20,21,22], but also mediates chondrocyte differentiation [23,24]. Furthermore, recent studies have revealed the capacity of AGEs to induce calcification by cultured SMCs and pericytes mediated by RAGE signaling [25,26,27]. RAGE signaling can be suppressed via ligand sequestration by endogenous secretory and endoproteolytically released soluble RAGE (sRAGE) [18,19,28,29,30].…”

Section: Introductionmentioning

confidence: 99%

Arterial Calcification Is Driven by RAGE in <i>Enpp1</i>–/– Mice

Cecil

Terkeltaub

2010

J Vasc Res

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Background/Aims: Ectopic osteochondral differentiation, driven by ENPP1-catalyzed generation of the chondrogenesis and calcification inhibitor inorganic pyrophosphate (PP_i), promotes generalized arterial calcification of infancy. The multiligand receptor for advanced glycation end-products (RAGE), which promotes atherosclerosis and diabetic cardiovascular and renal complications, also mediates chondrocyte differentiation in response to RAGE ligand calgranulins such as S100A11. Here, we tested RAGE involvement in ENPP1 deficiency-associated arterial calcification. Methods: Because ectopic artery calcification in Enpp1–/– mice is P_i-dependent and mediated by PP_i deficiency, in vitro studies on effects of S100A11 and RAGE on mouse aortic explants were conducted using exogenous P_i, as well as alkaline phosphatase to hydrolyze ambient PP_i. Results: S100A11 induced cartilage-specific collagen IX/XI expression and calcification dependent on RAGE in mouse aortic explants that was inhibited by the endogenous RAGE signaling inhibitor soluble RAGE (sRAGE). Enpp1–/– aortic explants demonstrated decreased P_i-stimulated release of sRAGE, and increased calcification and type IX/XI collagen expression that were suppressed by exogenous sRAGE and by Rage knockout. Last, Rage knockout suppressed spontaneous aortic calcification in situ in Enpp1–/– mice. Conclusion: Cultured Enpp1–/– aortic explants have decreased P_i-stimulated release of sRAGE, and RAGE promotes ectopic chondrogenic differentiation and arterial calcification in Enpp1–/– mice.

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“…These AGE-mediated changes in vascular smooth muscle cells were partially attenuated by a neutralizing antibody to RAGE. 19 AGE has also been shown to accelerate vascular calcification through the RAGE/ oxidative stress pathway in an animal model of diabetic vascular calcification. 20 Thus, our current novel clinical observations add to the growing experimental evidence linking AGE to vascular calcification and support the involvement of tissue AGE in the process of vascular calcification in CKD and diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Skin Autofluorescence Associates With Vascular Calcification in Chronic Kidney Disease

Wang

Wong

Yau

et al. 2014

ATVB

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Objective— This study aims to evaluate the relationship between tissue advanced glycation end products, as reflected by skin autofluorescence, and vascular calcification in chronic kidney disease. Approach and Results— Three hundred patients with stage 3 to 5 chronic kidney disease underwent multislice computed tomography to estimate total coronary artery calcium score (CACS) and had tissue advanced glycation end product assessed using a skin autofluorescence reader. Intact parathyroid hormone ( P <0.001) displaced estimated glomerular filtration rate as third most significant factor associated with skin autofluorescence after age ( P <0.001) and diabetes mellitus ( P <0.001) in multiple regression analysis. On univariate multinomial logistic regression analysis, every 1-U increase in skin autofluorescence was associated with a 7.43-fold (95% confidence intervals, 3.59–15.37; P <0.001) increased odds of having CACS ≥400 compared with those with zero CACS. Skin autofluorescence retained significance in predicting CACS ≥400 (odds ratio, 3.63; 95% confidence intervals, 1.44–9.18; P =0.006) when adjusting for age, sex, serum calcium, phosphate, albumin, C-reactive protein, lipids, blood pressure, estimated glomerular filtration rate, and intact parathyroid hormone but marginally lost significance when additionally adjusting for diabetes mellitus (odds ratio, 2.23; 95% confidence intervals, 0.81–6.14; P =0.1). Combination of diabetes mellitus and higher intact parathyroid hormone was associated with greater skin autofluorescence and CACS versus those without diabetes mellitus and having lower intact parathyroid hormone. Conclusions— Tissue advanced glycation end product, as reflected by skin autofluorescence, showed a significant novel association with vascular calcification in chronic kidney disease. These data suggest that increased tissue advanced glycation end product may contribute to vascular calcification in chronic kidney disease and diabetes mellitus and warrant further experimental investigation.

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Advanced Glycation End-products Enhance Calcification in Vascular Smooth Muscle Cells

Abstract: Advanced glycation end-products (AGEs

Cited by 59 publications

References 15 publications

High Glucose Concentration Does Not Modulate the Formation of Arterial Medial Calcification in Experimental Uremic Rats

High Glucose Concentration Does Not Modulate the Formation of Arterial Medial Calcification in Experimental Uremic Rats

Arterial Calcification Is Driven by RAGE in <i>Enpp1</i>–/– Mice

Skin Autofluorescence Associates With Vascular Calcification in Chronic Kidney Disease

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