{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:17:54Z","timestamp":1788445074257,"version":"build-2803163510"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,1,9]]},"abstract":"\n Background<\/jats:title>\n \n Cardiovascular disease is the leading cause of morbidity and mortality in patients with end\u2010stage renal disease. The accumulation of uremic solutes in this patient population is associated with endothelial dysfunction and accelerated cardiovascular disease. In this study, we examined the impact of the uremic milieu on the endothelial transcription factor, Kr\u00fcppel\u2010like factor 2 (\n KLF<\/jats:styled-content>\n 2), a key regulator of endothelial function and activation.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Using serum from uremic pigs with chronic renal insufficiency, our results show that\n KLF<\/jats:styled-content>\n 2 expression is suppressed by the uremic milieu and individual uremic solutes in\u00a0vitro. Specifically,\n KLF<\/jats:styled-content>\n 2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine\u2010modified albumin, an advanced glycation end product (\n AGE<\/jats:styled-content>\n ) known to induce endothelial dysfunction.\n AGE<\/jats:styled-content>\n \u2010mediated suppression of\n KLF<\/jats:styled-content>\n 2 is dependent on activation of the receptor for\n AGE<\/jats:styled-content>\n , as measured by small interfering\n RNA<\/jats:styled-content>\n knockdown of the receptor for\n AGE<\/jats:styled-content>\n . Furthermore,\n KLF<\/jats:styled-content>\n 2 suppression promotes endothelial dysfunction, because adenoviral overexpression of\n KLF<\/jats:styled-content>\n 2 inhibits reactive oxygen species production and leukocyte adhesion in human umbilical vein endothelial cells. In addition, the application of hemodynamic shear stress, prolonged serum dialysis, or treatment with the receptor for\n AGE<\/jats:styled-content>\n antagonist azeliragon (\n TTP<\/jats:styled-content>\n 488) is sufficient to prevent\n KLF<\/jats:styled-content>\n 2 suppression in\u00a0vitro. To decipher the mechanism by which uremic\n AGE<\/jats:styled-content>\n s suppress\n KLF<\/jats:styled-content>\n 2 expression, we assessed the role of the receptor for\n AGE<\/jats:styled-content>\n in activation of nuclear factor\u2010\u03baB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of I\u03baB\u03b1, we show that translocation of p65 to the nucleus is necessary for\n KLF<\/jats:styled-content>\n 2 suppression after treatment with uremic\n AGE<\/jats:styled-content>\n s.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These data identify\n KLF<\/jats:styled-content>\n 2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.117.007566","type":"journal-article","created":{"date-parts":[[2018,1,5]],"date-time":"2018-01-05T01:11:07Z","timestamp":1515114667000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Uremic Advanced Glycation End Products and Protein\u2010Bound Solutes Induce Endothelial Dysfunction Through Suppression of Kr\u00fcppel\u2010Like Factor 2"],"prefix":"10.1161","volume":"7","author":[{"given":"Keith","family":"Saum","sequence":"first","affiliation":[{"name":"University of Cincinnati Medical Scientist Training Program, The University of Cincinnati College of Medicine, Cincinnati, OH"},{"name":"Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bego\u00f1a","family":"Campos","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Celdran\u2010Bonafonte","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of Arizona College of Medicine and Banner University Medical Centers\u2013Tucson and South and Southern Arizona Veterans Affairs Healthcare System, Tucson, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalitha","family":"Nayak","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panjamaporn","family":"Sangwung","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Department of Medicine, Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charuhas","family":"Thakar","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabir","family":"Roy\u2010Chaudhury","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH"},{"name":"Division of Nephrology, University of Arizona College of Medicine and Banner University Medical Centers\u2013Tucson and South and Southern Arizona Veterans Affairs Healthcare System, Tucson, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III PhD","given":"A. 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