Active Focal Segmental Glomerulosclerosis Is Associated with Massive Oxidation of Plasma Albumin

Abstract

The basic mechanism for idiopathic FSGS still is obscure. Indirect evidence in humans and generation of FSGS by oxidants in experimental models suggest a role of free radicals. In vitro studies demonstrate a main role of plasma albumin as antioxidant, its modification representing a chemical marker of oxidative stress. With the use of complementary liquid chromatography electron spray ionization tandem mass spectrometry (LC-ESI-MS/MS) and biochemical methods, plasma albumin was characterized in 34 patients with FSGS; 18 had received a renal transplant, and 17 had IgM mesangial deposition. Patients with FSGS that was in remission or without recurrence after transplantation had normal plasma albumin, and the same occurred in patients with primary and secondary nephrites and with chronic renal failure. In contrast, patients with active FSGS or with posttransplantation recurrence had oxidized plasma albumin. This finding was based on the characterization of albumin Cys 34 with an mass-to-charge ratio of 511.71 in triple charge that was consistent with the formation of a cysteic acid carrying a sulfonic group (alb-SO 3 ؊ ). The exact mass of albumin was increased accordingly (؉48 Da) for incorporation of three oxygen radicals. Direct titration of the free sulfhydryl group 34 of plasma albumin and electrophoretic titration curves confirmed loss of free sulfhydryl group and formation of a fast-moving isoform in all cases with disease activity. This is the first demonstration of in vivo plasma albumin oxidation that was obtained with an adequate structural approach. Albumin oxidation seems to be specific for FSGS, suggesting some pathogenetic implications. Free radical involvement in FSGS may lead to specific therapeutic interventions.

Current Issues in Measurement and Reporting of Urinary Albumin Excretion

“…Reactions with amino acid side-chains yield carbonyl group, carboxymethyllysine, and advanced glycation end products on a small proportion of albumin molecules (76,84,85 ). Dityrosine cross-links also have been detected (77 ).…”

“…It has an unusually low pK of about 5 that results in increased reactivity and rates of disulfide-bond formation and exchange with other sulfhydryl-containing compounds in plasma (57,74,75 ). Albumin can form disulfide-linked dimers, with 2 albumin monomers linked by cysteine-34 residues, or the cysteine sidechain can be oxidized to a sulfonic acid (57,76 ). Albumin with various modifications of cysteine-34 has different binding properties for a variety of ligands, suggesting a significant conformational change (57,77 ).…”

Oxidation of the albumin thiol to sulfenic acid and its implications in the intravascular compartment

“…In fact, the fraction of oxidized albumin correlates with several pathologies. In patients with different renal diseases the level of oxidized albumin is increased (28,50,51). Recently, a progressive oxidative modification of albumin with increasing severity of liver failure has been reported (52).…”

Regulatory T cells and minimal change nephropathy: in the midst of a complex network

“…Albumin has only recently been recognized as the major anti-oxidant in serum, a physiological function that evolved over years and that confers a crucial role to this protein during infectious episodes in humans [21]. Musante et al [22] characterized serum albumin in children with MCN by mean of mass spectrometry, and showed chemical modifications of the unique free 34 Cys of the protein sequence to a sulphonic group (SO 3 H) that is the end product of its oxidation, and therefore represents a surrogate biomarker of an oxidative stress [22,23]. Animal models of nephrosis also support a role of oxidants.…”