Oxidized Albumin as a Mediator of Kidney Disease

Abstract

Renal diseases are a global health concern, and nearly 24% of kidney disease patients are overweight or obese. Particularly, increased body mass index has been correlated with oxidative stress and urinary albumin excretion in kidney disease patients, also contributing to increased cardiovascular risk. Albumin is the main plasma protein and is able to partially cross the glomerular filtration barrier, being reabsorbed mainly by the proximal tubule through different mechanisms. However, it has been demonstrated that albumin suffers different posttranslational modifications, including oxidation, which appears to be tightly linked to kidney damage progression and is increased in obese patients. Plasma-oxidized albumin levels correlate with a decrease in estimated glomerular filtration rate and an increase in blood urea nitrogen in patients with chronic kidney disease. Moreover, oxidized albumin in kidney disease patients is independently correlated with higher plasma levels of transforming growth factor beta (TGF-β1), tumor necrosis factor (TNF-α), and interleukin (IL)-1β and IL-6. In addition, oxidized albumin exerts a direct effect on neutrophils by augmenting the levels of neutrophil gelatinase-associated lipocalin, a well-accepted biomarker for renal damage in patients and in different experimental settings. Moreover, it has been suggested that albumin oxidation occurs at early stages of chronic kidney disease, accelerating the patient requirements for dialytic treatment during disease progression. In this review, we summarize the evidence supporting the role of overweight- and obesity-induced oxidative stress as a critical factor for the progression of renal disease and cardiovascular morbimortality through albumin oxidation.

Keywords: kidney disease; obesity; oxidized albumin.

Figure 1

Albumin structure and its tubular reabsorption. (A) Schematic drawing of the human serum albumin (HSA) structure. The mature HSA presents 585 amino acids and a molecular weight of 66.5 kDa, containing three homologous α-helical domains (I, II, and III), each comprised of two sub-domains A and B. Each sub-domain is represented by a rectangular bar with a unique color. The two Sudlow’s sites, high affinity binding sites for different molecules on HSA, are marked in black dashed lines. (B) Albumin is partially filtered in the glomeruli and reabsorbed by receptor-mediated endocytosis into proximal (71%) and distal tubule cells (26%). This schematic representation shows albumin internalization and its degradation in the proximal tubule. Albumin binds to the megalin–cubulin complex receptor and is directed into clathrin-coated vesicles for endocytosis. Following endocytosis, endosomal acidification occurs, which causes albumin dissociation from the megalin–cubulin complex, leading albumin to bind to the neonatal Fc receptor (FcRn). Finally, albumin is transferred to the lysosomal compartment for degradation (step a) or for the transcytotic pathway (step b), while the receptors may be recycled through dense apical tubules.

Figure 2

Albumin oxidation affects its properties in kidney damage. (A) Main residues on the active HSA sensitive to oxidation: Cys residue at position 34; Tyr residues 84, 138, 140, 161, 263, 319, 332, 334, 353, and 370; Met residues at positions 87 and 123; and Trp residue at position 214. Met-87 and Met-123 are most oxidized to methionine sulfoxide, particularly in kidney failure and diabetes. (B) Different types of Cys34 oxidation. Under oxidative stress induced by reactive oxygen species (ROS), albumin is oxidized and Cys34 forms a disulfide with a free cysteine or glutathione. The oxidation changes the HSA three-dimensional structure that influences binding of drugs, such as Sudlow’s site II. Depending on the extent of HSA oxidations, they can be classified as reversible (HNA-1) and irreversible (HNA-2), which may increase different pro-inflammatory cytokines and markers of kidney damage.

Figure 3

Reactive oxygen species (ROS) are increased in obese people, favoring the oxidized form of HSA (HNA), which in turns, generates an increase in proinflammatory cytokines. Here, we hypothesized (discontinuous lines) that the HNA, particularly oxidized at Cys34, may be generated as a result of obesity, promoting the progression of inflammatory and degenerative injuries, which are crucial for the progression of chronic kidney disease.