Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation.
OBJECTIVE
Advanced glycation end products, known pro-inflammatory and pro-oxidative compounds that accumulate in patients with chronic kidney disease, may play a major role in their high prevalence of endothelial dysfunction and subsequent cardiovascular disease. This study examined the association of advanced glycation end product accumulation with cellular receptor for advanced glycation end product expression and endothelial dysfunction as well as the mechanisms of this association in chronic kidney disease.


METHODS
A cross-sectional study was conducted of ambulatory patients without diabetes and with different stages of chronic kidney disease (n = 51), compared with gender- and age-matched healthy subjects. Fasting blood was obtained for measurement of advanced glycation end products and mRNA receptor for advanced glycation end product expression in peripheral blood mononuclear cells. Endothelial reactivity was assessed by the microcirculatory response to local ischemia (postocclusive reactive hyperemia) and local hyperthermia (thermal hyperemia). Sera were pooled and passed through affinity columns to separate advanced glycation end product-rich fractions, which were incubated with human aortic endothelial cells, with or without blockade of receptor for advanced glycation end product, to measure their effect on endothelial nitric oxide synthase.


RESULTS
Glomerular filtration rate correlated with serum advanced glycation end product, mRNA receptor for advanced glycation end product levels, postocclusive reactive hyperemia, and thermal hyperemia. Serum advanced glycation end product correlated with receptor for advanced glycation end product and inversely with postocclusive reactive hyperemia. Advanced glycation end product-rich fractions from chronic kidney disease sera suppressed endothelial nitric oxide synthase expression of human aortic endothelial cells compared with sera from healthy subjects, an effect abrogated by receptor for advanced glycation end product blockade.


CONCLUSIONS
This study demonstrates for the first time an association of excess advanced glycation end product burden with increased peripheral blood mononuclear cell mRNA receptor for advanced glycation end product and in vivo endothelial dysfunction in patients with chronic kidney disease. Endothelial dysfunction in chronic kidney disease may be partly mediated by advanced glycation end product-induced inhibition of endothelial nitric oxide synthase through receptor for advanced glycation end product activation.
Linden
Ellena
E
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
Cai
Weijing
W
He
John C
JC
Xue
Chen
C
Li
Zhu
Z
Winston
Jonathan
J
Vlassara
Helen
H
Uribarri
Jaime
J
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D006940:Hyperemia / Q000378:metabolism / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000097:blood; D034741:RNA, Small Interfering / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000503:physiopathology; D012720:Severity of Illness Index; D012867:Skin / Q000098:blood supply*; D015854:Up-Regulation
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D008239:Lysine