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The association between serum vitamin D levels and renal tubular dysfunction in a general population exposed to cadmium in China.

ABSTRACT: Cadmium exposure can cause renal tubular dysfunction. Recent studies show that vitamin D can play multiple roles in the body. However, the association between serum vitamin D levels and renal tubular dysfunction in a general population exposed to cadmium has not been clarified. We performed study to assess the effects of cadmium on serum 25(OH) D levels and the association between serum 25(OH) D levels and renal tubular dysfunction in a population environmentally exposed to cadmium. A total of 133 subjects living in control area and two cadmium polluted areas were included in the present study. Cadmium in urine (UCd) and blood (BCd), urinary β2Microglobulin (UBMG), urinary retinol binding protein (URBP) and serum 25 (OH) D were determined. Logistic regression was used to estimate the association between 25 (OH) D and prevalence of renal tubular dysfunction. No significant differences were observed in serum 25(OH) D levels among the four quartile of UCd and BCd after adjusting with cofounders. After adjusted with the confounders, the odds ratio (OR) of subjects with 25(OH) D ≥ 40 ng/ml were 0.20 (95%CI: 0.1-0.8) if UBMG was chosen as indicators of renal dysfunction and 0.28 (95%CI: 0.1-1.1) if URBP was chosen as indicators of renal dysfunction, compared with those with 25(OH) D < 30 ng/ml, respectively. Similar results were observed in those subjects living in cadmium polluted areas or with high level of UCd or BCd. Our data indicated that cadmium exposure did not affect serum 25(OH) D level and high 25 (OH) D levels were associated with a decreased risk of renal tubular dysfunction induced by cadmium.

SUBMITTER: Chen X

PROVIDER: S-EPMC5892922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A number of factors, including gender, age, smoking habits, and occupational exposure, affect the levels of urinary cadmium. Few studies have considered these influences when calculating the benchmark dose (BMD) of cadmium. In the present study, we aimed to calculate BMDs and their 95% lower confidence bounds (BMDLs) for cadmium-induced renal tubular effects in an age-specific population in south-central China.In this study, urinary cadmium, β2-microglobulin, and N-acetyl-β-D-glucosaminidase levels were measured in morning urine samples from 490 randomly selected non-smoking women aged 35-54 years. Participants were selected using stratified cluster sampling in two counties (counties A and B) in China. Multiple regression and logistic regression analyses were used to investigate the dose-response relationship between urinary cadmium levels and tubular effects. BMDs/BMDLs corresponding to an additional risk (benchmark response) of 5% and 10% were calculated with assumed cut-off values of the 84th and 90th percentile of urinary β2-microglobulin and N-acetyl-β-D-glucosaminidase levels of the controls.Urinary levels of β2-microglobulin and N-acetyl-β-D-glucosaminidase increased significantly with increasing levels of urinary cadmium. Age was not associated with urinary cadmium levels, possibly because of the narrow age range included in this study. Based on urinary β2-microglobulin and N-acetyl-β-D-glucosaminidase, BMDs and BMDLs of urinary cadmium ranged from 2.08 to 3.80 (1.41-2.18) µg/g cr for subjects in county A and from 0.99 to 3.34 (0.74-1.91) µg/g cr for those in county B. The predetermined benchmark response of 0.05 and the 90th percentiles of urinary β2-microglobulin and N-acetyl-β-D-glucosaminidase levels of the subjects not exposed to cadmium (i.e., the control group) served as cut-off values.The obtained BMDs of urinary cadmium were similar to the reference point of 1 µg/g cr, as suggested by the European Food Safety Authority, indicating that cadmium exposure must be reduced to protect human health.

Project description:We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl2), the level of Notch intracellular domain (NICD), the cleaved form of the Notch1 receptor, was increased and accumulated in the nuclear fraction. Knockdown of Notch1 with siRNA or treatment with the ?-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), prevented CdCl2-induced morphological change of HK-2 cells and reduction of cell viability. Knockdown of Jagged1 or Jagged2, the ligands of the Notch1 receptor, partially suppressed cadmium cytotoxicity. Inhibition of p53 activity with pifithrin-? or inhibition of PI3K with LY294002 suppressed CdCl2-induced cellular damage and elevation of Notch1-NICD. In addition, treatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, and the insulin-like growth factor-1 receptor inhibitor, PPP, suppressed both Notch1-NICD accumulation and Akt phosphorylation in HK-2 cells exposed to CdCl2. However, knockdown of Notch1 did not affect CdCl2-induced p53 accumulation and phosphorylation but suppressed phosphorylation of EGFR, Akt, and p70 S6 kinase. Depletion of Notch1 suppressed CdCl2-induced reduction of E-cadherin expression and elevation of Snail expression. Furthermore, treatment with SB216763, an inhibitor of glycogen synthase kinase-3, suppressed the potency of LY294002 treatment to reduce Snail expression in HK-2 cells exposed to CdCl2. Knockdown of Snail with siRNA partially prevented HK-2 cells from CdCl2-induced reduction of E-cadherin expression and cellular damage. These results suggest that cadmium exposure induces the activation of Notch1 signaling in renal proximal tubular cells with cooperative activation by the p53 and PI3K/Akt signaling pathways; the resultant expression of Snail, a repressor of E-cadherin expression, might lead to cellular damage by decreasing cell-cell adhesion.

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The association between serum vitamin D levels and renal tubular dysfunction in a general population exposed to cadmium in China.

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