Abstract
Chronic cadmium (Cd) exposure can induce renal toxicity. In Cd renal toxicity, p53 is thought to be involved. Our previous studies showed that Cd down-regulated gene expression of the UBE2D (ubiquitin-conjugating enzyme E2D) family members. Here, we aimed to define the association between UBE2D family members and p53-dependent apoptosis in human proximal tubular cells (HK-2 cells) treated with Cd. Cd increased intracellular p53 protein levels and decreased UBE2D2 and UBE2D4 gene expression via inhibition of YY1 and FOXF1 transcription factor activities. Double knockdown of UBE2D2 and UBE2D4 caused an increase in p53 protein levels, and knockdown of p53 attenuated not only Cd-induced apoptosis, but also Cd-induced apoptosis-related gene expression (BAX and PUMA). Additionally, the mice exposed to Cd for 6 months resulted in increased levels of p53 and induction of apoptosis in proximal tubular cells. These findings suggest that down-regulation of UBE2D family genes followed by accumulation of p53 in proximal tubular cells is an important mechanism for Cd-induced renal toxicity.
Highlights
Chronic cadmium (Cd) exposure can induce renal toxicity
We examined the effect of Cd on UBE2D family gene expression, the accumulation of p53 protein, and apoptosis in human proximal tubular cells (HK-2 cells)
As UBE2D family is involved in the stability of p53 in MCF7 cells[32], we examined the effect of Cd on UBE2D family gene expression in HK-2 cells
Summary
Chronic cadmium (Cd) exposure can induce renal toxicity. In Cd renal toxicity, p53 is thought to be involved. The mice exposed to Cd for 6 months resulted in increased levels of p53 and induction of apoptosis in proximal tubular cells These findings suggest that down-regulation of UBE2D family genes followed by accumulation of p53 in proximal tubular cells is an important mechanism for Cd-induced renal toxicity. In NRK-52E rat proximal tubular epithelial cells, Cd inhibited the gene expression of Ube2d4, a member of the UBE2D (ubiquitin-conjugating enzyme E2D) family[10]. We demonstrated that Cd increased phospho-p53 level and induced apoptosis in NRK-52E cells[16] These observations suggest that Cd-induced apoptosis may be cause of the accumulation of p53 protein, which in turn may be cause of the down-regulation of UBE2D family genes. Whether UBE2D family is involved in the degradation of p53, and whether p53 is associated with Cd-induced apoptosis in human proximal tubular cells remains to be elucidated
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