Abstract
Cadmium (Cd) is an environmental contaminant that exhibits renal toxicity. The target transcription factors involved in Cd renal toxicity are still unknown. In this study, we demonstrated that Cd decreased the activity of the ARNT transcription factor, and knockdown of ARNT significantly decreased the viability of human proximal tubular HK-2 cells. Microarray analysis in ARNT knockdown cells revealed a decrease in the expression of a number of genes, including a known apoptosis inhibitor, BIRC3, whose gene and protein expression level was also decreased by Cd treatment. Although the BIRC family consists of 8 members, Cd suppressed only BIRC3 gene expression. BIRC3 is known to suppress apoptosis through the inhibition effect on caspase-3. Knockdown of BIRC3 by siRNA as well as Cd treatment increased the level of active caspase-3. Moreover, knockdown of BIRC3 not only triggered cell toxicity and apoptosis but also strengthened Cd toxicity in HK-2 cells. Meanwhile, the activation of caspase-3 by suppression of BIRC3 gene expression was mostly specific to Cd and to proximal tubular cells. These results suggest that Cd induces apoptosis through the inhibition of ARNT-regulated BIRC3 in human proximal tubular cells.
Highlights
Cadmium (Cd) is an environmental contaminant that induces toxic effects in various tissues including the kidney[1,2,3]
Our results showed that binding activities of both p53 and MTF-1 transcription factors were increased in HK-2 cells in response to Cd treatment
Consistent with our results, several previous studies reported that PPAR and Sp-1 activities were decreased by Cd28,29
Summary
Cadmium (Cd) is an environmental contaminant that induces toxic effects in various tissues including the kidney[1,2,3]. Cd has been reported to have adverse effect on cellular functions, the precise mechanism of Cd-induced proximal tubular cell toxicity remains unclear. To elucidate the precise mechanism of Cd-induced renal toxicity, we previously used the DNA microarray method to screen genes whose expression is changed by Cd treatment in mouse kidney and cultured cells, including proximal tubular cells[11,12,13]. The upstream pathways that regulate gene transcription are controlled by specific regulatory mechanisms; not all genes are induced at the same time and with the same duration Some genes, such as those responsible for correct protein folding, are immediately induced for transcription within minutes; whereas others, such as those involved in DNA damage repair and cell metabolism, are slowly responded to upstream inductions signaling, within hours[21]. We examined the downstream factors of Cd-targeted transcription factors that are involved in Cd-induced renal toxicity
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