The Protector Of ​kidney Function: Selenium

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PART Ⅱ：The Aging Kidney—As Influenced by Heavy Metal Exposure and Selenium Supplementation

Jan Aaseth, Jan Alexander, Urban Alehagen, Alexey Tinkov, Anatoly Skalny, Anders Larsson, Guido Crisponi and Valeria Marina Nurchi

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5. Selenium—A Renal Protector with Chelating Properties

The process of aging appears to be related to a redox imbalance in cells characterized by increased ROS production or decreased efficacy of ROS scavenging, resulting in impaired cellular functions [5]. Supplementation of selenium in vivo has been reported to enhance antioxidant capacity, especially by increasing antioxidant enzyme activity,e.g., the activity of GPX[69]. Of particular interest is the observed increase in serum GPX3 upon selenium supplementation, as this selenoenzyme is formed in the kidneys and found accumulated in the basement membrane surrounding renal proximal tubules [70].

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A recent placebo-controlled study of an elderly Swedish population showed an association between low selenium (Se) status and age-related reduction in renal function [71]. In this study, dietary supplementation for four years with selenium 200 ug/day (as SelenoPre-case, Pharma Nord, Denmark) and coenzyme Q10, significantly improved kidney function as compared with the functional indices in the placebo group. The improvement of kidney function was attributed to the optimized function of antioxidative selenoenzymes such as GPXs and thioredoxin reductase, although it is known that selenol compounds can also act as strong chelating agents, e.g., against mercurials[72]. However, it should be noted that supra-nutritional intakes of selenium above about 300 μg/day may exert pro-oxidative effects |73L, and have been associated with increased risk of type 2 diabetes mellitus [74]Interestingly, low serum selenium is commonly reported in patients with advanced renal disease [75]. Low serum selenium levels in patients on hemodialysis or peritoneal dialysis have been ascribed to diminished selenium retention due to chronic oxidative stress [76]. In a recent study on a cohort with end-stage renal disease, patients with low serum selenium values（<63 μg/L） showed an increased mortality risk， as compared to patients with normal or high selenium（>118 μg/L）【7】. One important pathway of selenium to the kidney is the uptake of circulating selenoprotein-P fragments by megalin/LRP2 a multiligand receptor mediating endocytosis in the plasma membrane of the tubular cells [78,79]. This receptor, either alone or in concert with tubulin, functions as a receptor for reabsorption from primary urine of low molecular proteins, e.g., vitamin D binding protein [80], a function that may be compromised in tubular injury.

Mercury, as well as lead and cadmium, may be bound and detoxified by selenium compounds, mainly selenite or selenomethionine (Figure 3) [72].

Figure 3. Molecular formulae of (a) selenomethionine and (b)sodium selenite.

Several studies in humans have shown that administration of Se to individuals exposed to mercury reduced the severity of Hg intoxication [81]. However, it is not clear whether Hg-Se complexes are excretable forms of mercury. Of note, the binding affinity of mercury is greater for Se compounds than for thiols [15]. Sugiura et al. [82], from their NMR measurements, reported that the order of binding affinity of various selenium and sulfur donor groups toward methylmercury is in the order SeH>SH>Se-Se>S-S, SeCH3, SCH3.However， the concentration of selenium in the blood is only about 1 μmol/L 【83】 while the concentration of albumin-SH, Cys, and GSH in the blood is approximately 500,275, and 850 umol/L, respectively [84]. Since the normal blood SH-concentrations of albumin-SH and GSH(totally above1000 umol/L) are significantly greater than that of selenium, it appears reasonable that the major fraction of circulating mercury is bound to albumin and/or GSH rather than to Se-proteins, although a minor fraction of circulating mercury is coordinated to selenium compounds. A recent review of Spiller et al. [85]remarks, besides the role of selenium supplementation, the pros and cons of chelation, and the impact of chelation and selenium on the different forms of mercury.

6. Discussion and Conclusions

The aging process in the kidneys has been studied and characterized comprehensively. It is well known that glomerulosclerosis leads to decreased GFR. However, there is little information regarding the response of the aged kidneys to environmental toxicants such as mercury, cadmium, and lead. Due to the prevalence of mercury, cadmium, and lead in the environment, human exposure is practically unavoidable. Further, it is well known that not only acute but also chronic exposures to toxic metals may be detrimental to the kidneys of healthy adults. Available research indicates that long-term exposure of individuals with reduced GFR to these metals may result in additional reductions in renal function. Individuals with compromised renal function, either from aging, disease, or a combination of both, may be particularly susceptible to these toxicants. Available data show an association between exposure to mercury, cadmium, and lead and an increase in incidence and severity of renal disease. Of note, early signs of renal dysfunction often go unnoticed, which implies that individuals with reduced renal function are unaware that they may be at risk. Preliminary observations indicate that some physiological thiol amino acids, as well as adequate or supra-nutritional selenium supplementation, exert nephroprotective actions, but further studies are necessary on these therapeutic possibilities. Improved insights into the manner in which heavy metals are handled by aging kidneys are of utmost importance.

Author Contributions: Conceptualization, J.A.(Jan Aaseth), U.A.and A.T.; methodology, J.A.(Jan Aaseth) and J.A.(an Alexander); software, G.C.; validation, J.A.(Jan Aaseth), V.M.N.and A.L.; formal analysis, J.A.(Jan Aaseth) and V.M.N.; investigation, J.A.(Jan Aaseth) andJ.A.(an Alexander); resources, J.A.(Jan Aaseth), A.S., and V.M.N; writing—original draft preparation, J.A. (an Aaseth); writing—review and editing, J.A.(Jan Aaseth), and V.M.N.; visualization, G.C.; supervision, J.A. (Jan Aaseth); project administration, J.A.(Jan Aaseth); funding acquisition, J.A.(Jan Aaseth), V.M.N.and J.A.(Jan Alexander). All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding.

Prevention o renal failure: cistanche and selenium supplementation

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