Glutathionyl hemoglobin in uremic patients undergoing hemodialysis and continuous ambulatory peritoneal dialysis

Takayama, Fumio; Tsutsui, Shuichi; Horie, Masanobu; Shimokata, Kaoru; Niwa, Toshimitsu

doi:10.1046/j.1523-1755.2001.07834.x

Cited by 31 publications

(20 citation statements)

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“…We found high levels of HbSSG in cells of HD patients which in addition to being consistent with the parallel observation of diminished GSH/GSSG E h , confirm the presence of oxidative stress and point to an attempt of cell proteins to scavenge low molecular mass disulfides from the cytosol. S -glutathionylation of Hb, a rare event in healthy erythrocytes, 11 was reported in a number of pathologic conditions besides renal failure 23–25 including diabetes, hyperlipidemia and Friedreich’s ataxia. 2627, 2823 It is interpreted as a mechanism to regenerate reduced free GSH from disulfide GSSG and, ultimately, as a buffering defense mechanism against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance hemodialysis patients

Khazim

Giustarini

Rossi

et al. 2013

Translational Research

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Glutathione (GSH), the most abundant intracellular low molecular mass thiol, protects cells from oxidative damage and regulates their function. Available information is inconsistent regarding levels of GSH and its disulfide (GSSG) in maintenance hemodialysis patients (HD). In addition, very limited data are available in HD about the relationship of GSH and GSSG with other measures of thiol metabolism and with the clinical profile. We tested the hypothesis that erythrocyte GSH/GSSG redox potential (Eh) is lower in HD than in healthy controls (C), and that Eh correlates with posttranslational thiolation of hemoglobin (Hb) and with standard clinical parameters in HD. In cross-sectional comparison of 33 stable HD and 21 C, we found a net loss of reducing capacity in HD as indicated by low erythrocyte GSH/GSSG Eh (−257 ± 5.5 vs. −270 ± 5.6 mV, p=0.002). Glutathionylated Hb (HbSSG) was 46% higher in HD than C (19.3 ± 4.80 vs. 13.2 ± 2.79 pmol/mg Hb; p = 0.001) and cysteinylated Hb (HbSSCy) was >3-fold higher in HD than C [38.3 (29.0 – 63.3) vs. 11.5 (9.6 – 17.2) pmol/mg Hb; p = 0.001]. In multiple regression analysis of the HD cases, statistically significant associations were found between the GSH/GSSG Eh and the BUN (p = 0.001), creatinine (p = 0.015) and nPCR (p = 0.05), after adjusting for age, race/ethnicity and etiology of end-stage renal disease (ESRD). In conclusion, accurate and precise analysis of GSH, GSSG and mixed disulfides reveals loss of erythrocyte GSH/GSSG Eh, rise of both HbSSG and HbSSCy, and correlation of these thiols with measures of uremia and dietary protein intake.

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Section: Discussionmentioning

confidence: 99%

Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance hemodialysis patients

Khazim

Giustarini

Rossi

et al. 2013

Translational Research

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“…Glutathionyl-haemoglobin is increased in patients suffering from type I and type II diabetes, Friedreich's ataxia, hyperlipidemia, and uremia associated with haemodialysis or peritoneal dialysis [20,58,[61][62][63]. Differently, a decrease in the normal (basal) concentration of glutathionylhaemoglobin has been measured in children with Down's syndrome [64].…”

Section: S-glutathionylated Proteins In Human Diseasesmentioning

confidence: 99%

“…Friedreich's ataxia [39,58] Human immunodeficiency virus [52] Hyperlipidemia [61] Renal cell carcinoma [72] Type I diabetes [20,62] Type II diabetes [61] Uremia and hemodialysis or peritoneal dialysis [63] of haemoglobin can exist in human erythrocytes [67]. However, we have shown that inappropriate blood sample manipulation can lead to an artifactual increase in PSSGs, because many variables may affect the PSSG measurement: for instance, used reagents, incubation times with different substances, sample freezing, acid precipitation of proteins [20,40].…”

Section: Disease Referencesmentioning

confidence: 99%

S‐Glutathionylation: from redox regulation of protein functions to human diseases

Giustarini

Rossi

Milzani

et al. 2004

J Cellular Molecular Medi

269

198

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play an integral role in the modulation of several physiological functions but can also be potentially destructive if produced in excessive amounts. Protein cysteinyl thiols appear especially sensitive to ROS/RNS attack. Experimental evidence started to accumulate recently, documenting that S-glutathionylation occurs in a number of physiologically relevant situations, where it can produce discrete modulatory effects on protein function. The increasing evidence of functional changes resulting from this modification, and the growing number of proteins shown to be S-glutathionylated both in vitro and in vivo support this contention, and confirm this as an attractive area of research. S-glutathionylated proteins are now actively investigated with reference to problems of biological interest and as possible biomarkers of human diseases associated with oxidative/nitrosative stress.

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“…In healthy individuals, 1.2-16% of total hemoglobin (35-37) is glutathionylated (although these high estimates have been challenged by ref. 38), and various situations that cause oxidative stress exacerbate glutathionylation (36)(37)(38). The glutathionyl-hemoglobin adduct has lower cooperativity at halfsaturation and has a 4-to 10-fold higher oxygen affinity than hemoglobin A (39), making for poorer oxygen delivery to tissues.…”

Section: Requirement For Low Gssg Concentrations Is Capable Of Mediatmentioning

confidence: 99%

Evolution of enzymes in a series is driven by dissimilar functional demands

Salvador

Savageau

2006

Proc. Natl. Acad. Sci. U.S.A.

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That distinct enzyme activities in an unbranched metabolic pathway are evolutionarily tuned to a single functional requirement is a pervasive assumption. Here we test this assumption by examining the activities of two consecutively acting enzymes in human erythrocytes with an approach to quantitative evolutionary design that avoids the above-mentioned assumption. We previously found that avoidance of NADPH depletion during the pulses of oxidative load to which erythrocytes are normally exposed is the main functional requirement mediating selection for high glucose-6-phosphate dehydrogenase activity. In the present study, we find that, in contrast, the maintenance of oxidized glutathione at low concentrations is the main functional requirement mediating selection for high glutathione reductase activity. The results in this case show that, contrary to the assumption of a single functional requirement, natural selection for the normal activities of the distinct enzymes in the pathway is mediated by different requirements. On the other hand, the results agree with the more general principles that underlie our approach. Namely, that (i) the values of biochemical parameters evolve so as to fulfill the various performance requirements that are relevant to achieve high fitness, and (ii) these performance requirements can be inferred from quantitative systems theory considerations, informed by knowledge of specific aspects of the biochemistry, physiology, genetics, and ecology of the organism.human erythrocytes ͉ oxidative stress ͉ safety factors ͉ quantitative evolutionary design ͉ systems biology A lthough numerous mutations can drastically change the values of biochemical parameters such as enzyme activities, these values are often narrowly distributed in natural populations. This outcome owes largely to the interplay between constraints imposed by physicochemical laws and natural selection for good performance of the organism's biochemical circuits. The strength of natural selection in shaping the design of living organisms at the molecular level (1) is just beginning to be appreciated. In humans, natural selection is strong enough to almost prevent fixation of mutations that decrease fitness by Ͼ0.002%. Furthermore, Ͼ70% of the amino acid-changing mutations are selected against (2, 3). In the many organisms that have larger effective populations, even smaller fitness differentials can drive natural selection. Understanding the quantitative design for biochemical parameters that has been achieved through natural selection (i.e., the qualitative and quantitative functional requirements that mediate their evolutionary tuning) is a goal of systems biology with far-reaching implications. Such understanding would provide valuable insight regarding physiological as well as evolutionary adaptation (4, 5) and guidance for metabolic engineering (6). However, this type of understanding for parameters such as enzyme activities remains limited.The assumption that the distinct enzyme activities in a metabolic pathway are evolutio...

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Glutathionyl hemoglobin in uremic patients undergoing hemodialysis and continuous ambulatory peritoneal dialysis

Abstract: Glutathionyl Hb levels were increased in HD and CAPD patients, probably because of enhanced oxidative stress. The measurement of glutathionyl Hb may be useful to assess oxidative stress in uremic patients.

Cited by 31 publications

References 0 publications

Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance hemodialysis patients

Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance hemodialysis patients

S‐Glutathionylation: from redox regulation of protein functions to human diseases

Evolution of enzymes in a series is driven by dissimilar functional demands

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