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Involvement of ERK MAPK signaling pathway in cisplatin-induced mitophagy and autophagic cell stress in renal tubular epithelial cells

Nephrotoxicity is the most common side effect and doselimiting factor in patients receiving cisplatin (CP) chemotherapy. Due to high energy requirements, renal tubular epithelial cells are rich in mitochondria which are highly damaged by CP. Damaged mitochondria undergo their removal, mitophagy, but they are also strongly implicated in apoptosis induction. Mitogenactivated protein kinases (MAPK) are key participants in CPinduced nephrotoxicity. Extracellular signalregulated protein kinase 1/2 (ERK1/2) has been shown to localize on mitochondria and is suspected to be involved in the regulation of mitophagy. It is currently unclear whether ERK 1/2 promotes generalized or mitochondria aselective autophagy, or whether mitochondrial localization of activated ERK is essential in CP nephrotoxicity. Here we show the timeline of events induced by CP in Human renal proximal tubular cells (HK2) at 3, 6, 12, and 24 hour treatment by monitoring the expression of various proteins involved in injury (LC3B1/2, p62, Beclin1, Atg5, Atg512, Pink, Parkin, Tom20, AMPK, PARP, Caspase 3, 9, and 8, Bax, Bcl2 and CyclinD1). Mitophagy is activated in the early stages of CP damage as a protective event after which there is a turnover to apoptosis and autophagic cell stress. The role of Parkin in mitophagy turnover to apoptosis induction has also been clarified. ERK 1/2 is activated in the early stages of CP treatment and shifts its localization towards the nucleus and plays a roll both in mitophagy, autophagy, and apoptosis. Additionally, we tested MEK inhibitor, Mirdametinib, and an ERK signaling pathway activator, Ceramide C6, and their influence on cell survival as well as the ERK 1/2 mitochondrial translocation under combinatory treatments. Smart targeting of molecules involved in CP nephrotoxicity should enable a new approach to nephrotoxicity prevention and potential application in the pharmaceutical industry.

ERK ; MAPK ; Cisplatin ; Mitophagy ; Apoptosis ; Kidney

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