The Role of Macrophage Migration Inhibitory Factor in Cisplatin-induced Acute Kidney Injury
| Autor: | Yu-HueiLin, 林玉慧 |
|---|---|
| Rok vydání: | 2012 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 100 Anticancer agent cisplatin causes acute kidney injury (AKI) following renal inflammation and nephrotoxicity including renal cell apoptosis and acute tubular necrosis. In this study, we investigated a novel role of glycogen synthase kinase (GSK)-3-facilitated nephrotoxicity followed by macrophage migration inhibitory factor (MIF)-mediated renal inflammation in cisplatin AKI. Pharmacologically inhibiting MIF abated cisplatin AKI in vivo; however, MIF expression was not required for cisplatin-induced tubular cell apoptosis in vitro. Immunohistochemistry showed a specific renal expression of MIF in cortical tubular cells and cisplatin caused MIF decrease from these cells. Accompanied by cisplatin nephrotoxicity in vivo and in vitro, cortical tubular cell MIF was lost and/or secreted from intracellular to extracellular sites. In vitro studies showed that activation of caspases, induction of DNA damage responses, and signaling pathways of epidermal growth factor receptor/Src/protein kinase C-δ/reactive oxygen species/p38 mitogen-activated proten kinase/c-Jun N-terminal kinase were all regulated for cisplatin cytotoxicity as well as MIF secretion. Notably, cisplatin activated GSK-3 followed by MIF secretion and induced GSK-3-regulated nephrotoxicity and renal inflammation. Once GSK-3 was also required for cisplatin-induced anticancer, as demonstrated in a cisplatin-based anticancer model, inhibiting MIF prevented AKI without interference on anticancer efficacy. These results not only prove the molecular mechanisms for GSK-3-regulated nephrotoxicity and MIF-regulated renal inflammation but also confer a therapeutic strategy by inhibiting cytotoxicity-associated MIF to ameliorate cisplatin AKI. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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