Uremic Advanced Glycation End Products and Protein‐Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel‐Like Factor 2

Abstract

BackgroundCardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage 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, Krüppel‐like factor 2 (KLF2), a key regulator of endothelial function and activation.Methods and ResultsUsing serum from uremic pigs with chronic renal insufficiency, our results show that KLF2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically, KLF2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine‐modified albumin, an advanced glycation end product (AGE) known to induce endothelial dysfunction. AGE‐mediated suppression of KLF2 is dependent on activation of the receptor for AGE, as measured by small interfering RNA knockdown of the receptor for AGE. Furthermore, KLF2 suppression promotes endothelial dysfunction, because adenoviral overexpression of KLF2 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 AGE antagonist azeliragon (TTP488) is sufficient to prevent KLF2 suppression in vitro. To decipher the mechanism by which uremic AGEs suppress KLF2 expression, we assessed the role of the receptor for AGE in activation of nuclear factor‐κB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of IκBα, we show that translocation of p65 to the nucleus is necessary for KLF2 suppression after treatment with uremic AGEs.ConclusionsThese data identify KLF2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.

Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease

“…The endothelium in CKD patients suffers from a continuous insult causing its activation and injury that may end in a dysfunctional state ( Figure 1 ). The endothelial activation in CKD is attributed to the pulsatile blood flow and disturbed shear stress [ 36 ], accumulation of uremic toxins, such as dimethyl arginines [ 37 , 38 ], indoxyl sulfate (IS) [ 39 , 40 , 41 ], indole-3 acetic acid (IAA) [ 21 , 42 ], kynurenine [ 20 , 43 , 44 ], p-cresol [ 45 , 46 ], trimethylamine-N-oxide (TMAO) [ 41 , 47 ], oxidized low-density lipoprotein (LDL) cholesterol particles [ 48 ], carbamylated lipoproteins [ 49 , 50 ], reactive oxygen species (ROS) [ 39 , 51 , 52 ], advanced glycation end-products (AGEs) [ 53 , 54 ], hyperhomocysteinemia [ 55 , 56 ], hyperphosphatemia [ 57 , 58 ], bacterial lipopolysaccharides or other bacterial products [ 59 , 60 , 61 ], endogenous damage-associated molecules, and proinflammatory cytokines [ 62 , 63 , 64 , 65 , 66 ], which all together constitute the uremic environment.…”

Indoxil sulfato induce senescencia y liberación de microvesículas en células endoteliales que promueven la calcificación vascular

“…Como se ha comentado, las toxinas urémicas promueven la disfunción endotelial en pacientes con ERC. Esto se ve evidenciado por el hecho de que, entre otras células, las células endoteliales experimentan una senescencia prematura inducida por toxinas urémicas [25][26][27]. El tratamiento con IS restringe el número de divisiones celulares que ocurren y hacen que las células endoteliales alcancen senescencia prematura inducida por estrés (conocido en inglés como SIPS), que se caracteriza por una detención irreversible en el ciclo celular [28].…”

How do Uremic Toxins Affect the Endothelium?

“…The expression of molecules with protective functions in endothelial cells may be altered in uremic conditions. For example, Krüppel-like factor 2 (KLF2) expression, an important transcription factor for endothelial homeostasis, is suppressed by PCS, IS, AGEs, and uremic serum [ 90 , 91 ]. In a similar manner, IS and uremic serum reduce the expression of sirtuin 1 (SIRT1), which plays an important role in maintaining endothelial functions, inhibiting senescence and oxidative stress [ 72 , 91 ].…”