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| Content Provider | Springer Nature Link |
|---|---|
| Author | Gong, Xuezhong Ivav, Vladimir N. Hei, Tom K. |
| Copyright Year | 2015 |
| Abstract | Our recent study demonstrated that sodium arsenite at a clinically relevant dose induced nephrotoxicity in human renal proximal tubular epithelial cell line HK-2, which could be inhibited by natural product 2,3,5,6-tetramethylpyrazine (TMP) with antioxidant activity. The present study demonstrated that arsenic exposure resulted in protein and enzymatic induction of heme oxygenase-1 (HO-1) in dose- and time-dependent manners in HK-2 cells. Blocking HO-1 enzymatic activity by zinc protoporphyrin (ZnPP) augmented arsenic-induced apoptosis, ROS production and mitochondrial dysfunction, suggesting a critical role for HO-1 as a renal protectant in this procession. On the other hand, TMP, upstream of HO-1, inhibited arsenic-induced ROS production and ROS-dependent HO-1 expression. TMP also prevented mitochondria dysfunction and suppressed activation of the intrinsic apoptotic pathway in HK-2 cells. Our results revealed that the regulation of arsenic-induced HO-1 expression was performed through multiple ROS-dependent signal pathways and the corresponding transcription factors, including p38 MAPK and JNK (but not ERK), AP-1, Nrf2 and NF-κB. TMP inhibited arsenic-induced activations of JNK, p38 MAPK, ERK, AP-1 and Nrf2 and block HO-1 protein expression. The present study, furthermore, demonstrated arsenic-induced expression of arsenic response protein 2 (ARS2) that was regulated by p38 MAPK, ERK and NF-κB. To our knowledge, this is the first report showing that ARS2 involved in arsenic-induced nephrotoxicity, while TMP pretreatment prevented such an up-regulation of ARS2 in HK-2 cells. Given ARS2 and HO-1 sharing the similar regulation mechanism, we speculated that ARS2 might also mediate cell survival in this procession. In summary, our study highlighted a role of HO-1 in the protection against arsenic-induced cytotoxicity downstream from the primary targets of TMP and further indicated that TMP may be used as a potential therapeutic agent in the treatment of arsenic-induced nephrotoxicity. |
| Starting Page | 2187 |
| Ending Page | 2200 |
| Page Count | 14 |
| File Format | |
| ISSN | 03405761 |
| Journal | Archives of Toxicology |
| Volume Number | 90 |
| Issue Number | 9 |
| e-ISSN | 14320738 |
| Language | English |
| Publisher | Springer Berlin Heidelberg |
| Publisher Date | 2015-09-24 |
| Publisher Place | Berlin, Heidelberg |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Sodium arsenite Tetramethylpyrazine (TMP) Nephrotoxicity Mitochondrial dysfunction Inducible heme oxygenase-1 (HO-1) Arsenic response protein 2 (ARS2) Nuclear factor erythroid derived-2 (Nrf2) Pharmacology/Toxicology Occupational Medicine/Industrial Medicine Environmental Health Biomedicine general |
| Content Type | Text |
| Resource Type | Article |
| Subject | Health, Toxicology and Mutagenesis Medicine Toxicology |
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