HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype - PubMed (original) (raw)

. 2014 Nov;25(11):2658-68.

doi: 10.1681/ASN.2013111212. Epub 2014 May 22.

Thimoteus Speer 2, Sophie Colin 3, Marietta Charakida 4, Stephen Zewinger 2, Bart Staels 3, Giulia Chinetti-Gbaguidi 3, Inga Hettrich 2, Lucia Rohrer 5, Francis O'Neill 4, Eve McLoughlin 4, David Long 6, Catherine M Shanahan 7, Ulf Landmesser 8, Danilo Fliser 2, John E Deanfield 4

Affiliations

HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype

Rukshana Shroff et al. J Am Soc Nephrol. 2014 Nov.

Abstract

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2-5 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.

Copyright © 2014 by the American Society of Nephrology.

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Figures

Figure 1.

Figure 1.

Endothelial effects of HDL in healthy controls and children with CKD stages 2–5, on dialysis and after transplantation. (A) Endothelial NO production (measured by ESR spectroscopy) in HAECs incubated with HDL (50 _µ_g/ml, 60 minutes). (B) Endothelial SO production (measured by ESR spectroscopy) in HAECs treated with HDL (50 _µ_g/ml, 60 minutes). (C) Endothelial VCAM-1 expression (determined by Western blot analysis and normalized to expression of GAPDH) in HAECs preincubated with HDL (50 _µ_g/ml, 60 minutes) and stimulated with TNF-α (0.1 ng/ml, 4 hours). (D) Cholesterol efflux from cholesterol-loaded J774 macrophages to apoB-depleted serum. Bar shows mean level in each group. Some data have similar values and therefore the dots may not equal the sample size. ESR, electron spin resonance; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Figure 2.

Figure 2.

Association between HDL functionality, eGFR, and different treatment regimens. (A) Endothelial NO production in HAECs treated with HDL (50 _µ_g/ml, 1 hour) from children on hemodialysis and peritoneal dialysis. (B) Endothelial NO production in HAECs incubated with HDL (50 _µ_g/ml, 1 hour) obtained from children before and immediately after hemodialysis. Bar shows mean level in each group.

Figure 3.

Figure 3.

Association between HDL function and circulating markers of vascular dysfunction in children with CKD. Association between _HDLCKD_-induced endothelial NO production and serum urate levels (A), serum angiopoietin-2 levels (B), and serum IL-6 levels (C) (_n_=36). Some data have similar values and therefore the dots may not equal the sample size.

Figure 4.

Figure 4.

Association between _HDLCKD_-induced NO production and aPWV and cIMT. (A) aPWV measured by applanation tonometry. (B) cIMT measured by an ultrasonography scan of the common carotid artery. Some data have similar values and therefore the dots may not equal the sample size.

Figure 5.

Figure 5.

Levels of SDMA measured by HPLC-ESI-MS/MS in children with CKD stages 2–5, on dialysis and after transplantation and in healthy controls. (A) Serum SDMA levels. (B) SDMA in the HDL fraction. (C) Association between HDL-associated SDMA and HDL-induced endothelial NO production. (D) Association between HDL-associated SDMA and HDL-induced endothelial SO production. Bar shows mean level in each group. HPLC-ESI-MS/MS, HPLC with electrospray ionization coupled to tandem mass spectrometry.

Figure 6.

Figure 6.

Longitudinal changes in the vascular effects of HDL in children on dialysis and 3 months after a kidney transplant. Endothelial NO production (A) and endothelial SO production (B) in HAECs incubated with HDL (50 _µ_g/ml, 1 hour) determined by ESR spectroscopy. (C) Endothelial VCAM-1 expression in HAECs preincubated with HDL (50 _µ_g/ml, 1 hour) and stimulated with TNF-α (0.1 ng/ml, 4 hours) determined by Western blot analysis and normalized to expression of GAPDH. (D) Cholesterol efflux from cholesterol-loaded J774 macrophages to apoB-depleted serum. Bar shows mean level in each group. ESR, electron spin resonance; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

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