Higher blood levels of the selenoprotein Glutathione Peroxidase-3 (GPx3) are positively associated with good renal function and are inversely associated with cardiovascular and all-cause mortality. Those are the main findings of a sub-analysis of data from the Swedish KiSel-10 study. The KiSel-10 study researchers investigated the effect of combined selenium and coenzyme Q10 supplementation on mortality in elderly community-living individuals low in selenium [Alexander 2024].
GPx3 is a member of a family of eight known glutathione peroxidase antioxidant enzymes. GPx3 catalyzes the conversion of hydrogen peroxide into water. Accordingly, it reduces the extent of oxidative damage to cells. In addition to its oxidoreductase role, GPx3 plays a role in metabolism regulation, in cell growth, in apoptosis, and in signal transduction. In some cancers, it may act as a tumor suppressor [Zhang 2024].
GPx3 Dependent Upon Selenium Intake and Kidney Function
GPx3 is an interesting selenoenzyme. Circulating GPx3 comes mainly from GPx3 bio-synthesis in the kidneys. Thus, the level of GPx3 activity in serum depends both on the dietary intake of selenium and on the ability of the kidneys to synthesize GPx3 [Alexander 2024].
The primary selenium transporter in the blood, the selenoprotein P, delivers selenium to the kidneys. How well the kidneys function will influence the supply of adequate quantities of GPx3 to the blood circulation [Alexander 2024].
At baseline, the KiSel-10 study participants had low-selenium status. Accordingly, at the start of the study, the level of serum GPx3 was mostly
dependent upon selenium status. Most of the study participants had normal or less severe reduced renal function [Alexander 2024].
In the placebo group, there was an association between GPx3 level and both serum selenium and serum selenoprotein P levels at inclusion and after 48 months. However, in the active treatment group, changes in various parameters of renal function associated with increases in circulating GPx3 concentrations indicated that kidney function also influences serum GPx3 activity [Alexander 2024].
Causal Relationship Between GPx3 and Renal Function
In the active treatment group of participants who took 200 mcg selenium daily for four years, the researchers observed that both GPx3 activity and renal function increased. Moreover, the increases in GPx3 activity were associated with corresponding increases in renal function. Put another way, variations in renal function seem to be associated with variations in GPx3 expression and activity. In this KiSel-10 sub-study, the selenium supplementation improved renal function and increased GPx3 in all three tertiles when the data were stratified according to GPx3 level [Alexander 2024].
Relationship Between GPx3 and Mortality
The study data showed that low GPx3 activity was associated with an increased risk of mortality that was dependent upon selenium status and
independent of renal function [Alexander 2024].
All-cause mortality
When the researchers stratified the study participants according to GPx3 expression level, they found a significantly higher all-cause mortality in the lowest GPx3 quartile 1 compared with the higher GPx3 quartiles 2–4 in the placebo group. They observed the same significantly higher all-cause mortality in Quartile 1 in the active treatment group as well. However, the active treatment group had lower all-cause mortality in Quartile 1 and in Quartiles 2–4 than was observed in the placebo group [Alexander 2024].
Cardiovascular mortality
Again, when the researchers stratified the study participants according to GPx3 expression, they found significantly higher cardiovascular mortality in the lowest GPx3 quartile, Quartile 1, as compared to the GPx3 quartiles 2‒4 of the placebo group. They observed the same significant relationship in the active treatment group. But, compared to the placebo group, the active treatment group had lower cardiovascular mortality rates in both Quartile 1 and Quartiles 2‒4 [Alexander 2024].
Low Serum Selenium and Low GPx3 at the Study Start
The level of circulating GPx3 at the beginning of the intervention in the KiSel-10 study would have been mostly dependent on selenium intake. Most of the study participants did have normal or less severe reduced renal function at the start of the study [Alexander 2024].
The supplementation with 200 mcg/day of selenium from selenium-enriched yeast plus an estimated 35 mcg/day of selenium from food raised the study participants’ serum selenium concentrations well above the level needed for maximum GPx3 expression. In this sub-analysis, the researchers determined that full GPX3 expression occurred at serum selenium levels of 100 mcg/L [Alexander 2024].
In a 2020 analysis of KiSel-10 data, Prof. Urban Alehagen and the research team reported that low selenium status was significantly related to impaired renal function. Supplementation with selenium resulted in significantly improved renal function as seen in creatinine levels and cystatin-C levels and through the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm [Alehagen 2020].
Conclusion: Selenium Status and Kidney Function Inter-Related
In unsupplemented elderly citizens with serum selenium concentrations below 100 mcg/L, serum GPx3 activity was dependent on selenium status and renal function.
Low GPx3 expression was associated with an increased relative risk of cardiovascular and all-cause mortality. The risk was independent of selenium status and renal function.
In elderly citizens supplemented with a selenium-enriched yeast preparation, serum GPx3 achieved maximum expression. Thereafter, serum GPx3 activity was dependent on renal function and other
regulating factors.
The increase in GPx3 expression following supplementation was associated with improvement in renal function.
Sources
Alexander J, Aaseth JO, Schomburg L, Chillon TS, Larsson A, Alehagen U. Circulating glutathione peroxidase-3 in elderly-association with renal function, cardiovascular mortality, and impact of selenium and coenzyme q10 supplementation. Antioxidants (Basel). 2024 Dec 19;13(12):1566.
Alehagen U, Brismar K, Alexander J, Aaseth J. Selenium and Coenzyme Q10 supplementation improves renal function in elderly deficient in selenium: observational results and results from a subgroup analysis of a randomized placebo controlled trial. Nutrients. 2020;12(12):3780.
Zhang N, Liao H, Lin Z, Tang Q. Insights into the role of glutathione peroxidase 3 in non-neoplastic diseases. Biomolecules. 2024;14:689.
The information presented in this review article is not intended as medical advice. It should not be used as such.