, 2011) has been observed. Interestingly, in our hands activity of NFκB was not affected but we observed HIF induction after

AAI delivery. These data are in accordance with results from animal studies. The presence of hypoxia was also observed in male Wistar rats treated with AAI for 4 days (Cao et al., 2010). In rat model AA evoked elevated nuclear staining for HIF-1α with concomitant reduction Ixazomib solubility dmso in VEGF production in long (8–16 weeks) (Sun et al., 2006a and Sun et al., 2006b) and short (4–7 days) term (Wen et al., 2008) experiments. Moreover, this increase of nuclear HIF-1α was present in the tubular cells in damaged area (Wen et al., 2008). However, in our studies concomitantly with HIF stabilization we observed elevation of VEGF production. The discrepancies between our results and published data may come from different time of stimulation and species-dependent differences in response. Additionally, it is possible that in case of longer AA treatment other transcription factors known to regulate VEGF expression, Selleckchem Afatinib like AP-1, may play a role. Therefore, it seems that regulation of VEGF expression after delivery of AAI is much more complex. Thus,

the understanding of the sequence of events evoked by AA is important to identify the origin of AAN development and still needs to be clarified. The most important part of our study is the discovering of the possible mechanism of AAI/OTA action on VEGF production. The augmentation of HIFs and SP-1 transcription factors activity by AAI was paralleled with the up-regulation of VEGF transcription and protein level. By the use of mithramycin A, an inhibitor of SP-1 activity, and chetomin, an inhibitor Bumetanide of HIFs, we showed that AAI-elevated VEGF production is reversed after inhibition of SP-1 and HIFs, what confirms the role of these transcription factors in the effect of AAI on VEGF expression. The next salient finding of our study is that hypoxia attenuated the inhibitory effect of OTA on VEGF production. In the kidney the localization of HIF isoforms depends

on cell type with HIF-1α presence in the tubular epithelia, whereas HIF-2α expression mostly in endothelial, glomerular and interstitial cells (Rosenberger et al., 2005). Although different role of HIF isoforms in kidney development may be the result of divergent localization in cells, it is well documented that HIF-1 and HIF-2 also differs in regulation of gene expression (reviewed in Loboda et al., 2010). HIF stabilization elevates angiogenesis and therefore it may attenuate adverse effects of toxins delivery. On the other hand, HIF triggers also the expression of connective tissue growth factor (CTGF), which exhibit profibrotic effects (Higgins et al., 2004). Thus, long-term activation of HIF may lead to fibrosis development. Therefore the proper balance in HIF activation is crucial for therapeutic effect.