Sarcopenia in Chronic Kidney Disease: Focus on Advanced Glycation End Products as Mediators and Markers of Oxidative Stress

Abstract

Sarcopenia is common in chronic kidney disease (CKD), and it is independently associated with morbidity and mortality. Advanced glycation end products (AGE) are mainly known as aging products. In CKD, AGE accumulate due to increased production and reduced kidney excretion. The imbalance between oxidant/antioxidant capacities in CKD patients is one of the main factors leading to AGE synthesis. AGE can, in turn, promote CKD progression and CKD-related complications by increasing reactive oxygen species generation, inducing inflammation, and promoting fibrosis. All these derangements can further increase AGE and uremic toxin accumulation and promote loss of muscle mass and function. Since the link between AGE and sarcopenia in CKD is far from being fully understood, we revised hereby the data supporting the potential contribution of AGE as mediators of oxidative stress in the pathogenesis of sarcopenia. Understanding how AGE and oxidative stress impact the onset of sarcopenia in CKD may help to identify new potential markers of disease progression and/or therapeutic targets.

Keywords: advanced glycation end products (AGE); chronic kidney disease; oxidative stress; sarcopenia.

Figure 1

Biochemical reactions leading to advanced glycation end product (AGE) formation. Glucose may lead to AGE formation through the Maillard reaction (1) and the polyol pathway (2). This last mainly occurs in conditions of excessive glucose, which is converted into fructose. AGE can also be formed by reactive carbonyl species generated by lipid peroxidation in conditions of excessive oxidative stress and further reactions with nucleophilic residues of macromolecules (3). ROS, reactive oxygen species; PUFA, polyunsaturated fatty acids.

Figure 2

Advanced glycation end products (AGE) in chronic kidney disease (CKD). AGE contributes to CKD progression by increasing reactive oxygen species (ROS) generation, up-regulating the expression of the receptor for advanced glycation end products (RAGE), and inducing inflammation and fibrosis, all mechanisms affecting glomerular function. Indeed, this activates a vicious circle that increases AGE and uremic toxin accumulation and oxidative stress and promotes loss of muscle mass and function.

Figure 3

Membrane RAGE (receptor for advanced glycation end products) and its soluble forms esRAGE (endogenous secretory RAGE) and cRAGE (cleaved RAGE). RAGE activation promotes a pro-inflammatory response and additional changes in normal cell functions which induce organ damages. At increasing ligands, membrane RAGE expression is upregulated, and this activates a vicious circle that increases the intracellular synthesis of reactive oxygen species (ROS) and the RAGE-mediated response. Circulating sRAGE, which include esRAGE and cRAGE, can block ligand binding to RAGE, thus playing a role as a decoy receptor. HMGB1, High Mobility Group Box 1; S-100 proteins, a family of 21 proteins structurally similar to calmodulin and considered to be damage-associated molecular pattern molecules; ERK1/2, extracellular signal-regulated protein kinase 1/2; p38, p38 mitogen-activated protein kinase; JNK/SAPK, c-Jun N-terminal kinase/stress-activated protein kinase; PI3K, phosphoinositide 3-kinases; JAK/STAT, Janus kinase/signal transducers and activators of transcription; NF-kB, nuclear factor-kB.

Figure 4

Advanced glycation end products (AGE), mitochondrial disfunction, and sarcopenia. AGE and reactive oxygen species (ROS) can affect mitochondrial function by decreasing oxidative enzymes and inducing oxidative alteration of mitochondrial proteins, which result in protein degradation and loss of function as well as lower mitochondrial (mt) volume density and mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial biogenesis/mass. These mechanisms lead to reduced mitochondrial function, which in turn could induce a state of muscle atrophy.

Figure 5

Advanced glycation end products (AGE) and insulin resistance. AGE can affect insulin signaling both directly and indirectly by increasing the circulating levels of reactive oxygen species and pro-inflammatory mediators. AGE can reduce insulin sensitivity by inhibiting the tyrosine kinase activity of the insulin receptor and reducing GLUT4 (Glucose Transporter Type 4) translocation. Accumulation of AGE overstimulates receptors for advanced glycation end product (RAGE) signaling which, along with contributing to fiber damage, recruitment of pro-inflammatory macrophages, and inflammation, may also exacerbate insulin resistance.