Cisplatin (CIS)-mediated nephrotoxicity is induced via transforming growth factor-beta (TGF-β) and TGF-β-activated kinase (TAK1). TGF-β and TAK1 are known to interact with microRNA-let-7b and microRNA-26b, respectively. Additionally, TGF-β1 is reported to down-regulate the autophagy marker microtubule-associated protein 1 light chain 3-II (LC3-II) through upregulation of microRNA-34a. Pentoxifylline (PTX) anti-inflammatory effects are mediated via suppressing TGF-β and regulating mammalian target of rapamycin (mTOR). The current study aimed to investigate the involvement of microRNAs let-7b, 26b, and 34a, and the modulating impact of PTX on CIS-induced nephrotoxicity. Moreover, we aimed at examining the ability of PTX to interact with TGF-β receptor-1 (TGFβR-1), and TAK1, and examine its ability to downgrade the previously reported toxicities. Hence, the expression of the aforementioned microRNAs, and protein levels of TGFβR-1, TGF-β1, TAK1, mTOR, LC3-II, and NF-κB were assessed. Molecular docking studies of PTX on TGFβR-1 and TAK1 were also executed. CIS induced TGF-β1, with down-regulation of microRNA-let-7b and -26b, and up-regulation of microRNA-34a. TGFβR-1, TAK1, and mTOR levels were increased, while LC3-II level was decreased. PTX significantly protected renal cells against CIS-induced changes as indicated by reverting the level of the investigated parameters, while exhibiting an antagonistic effect on TGFβR-1 and TAK1. Our results postulate a possible role of epigenetic regulation of CIS-induced nephrotoxicity through the investigated microRNAs proposing them as potential future targets for controlling this serious toxicity. PTX was able to shield CIS-induced toxicity possibly through blocking TGF-β pathway, while promoting autophagy in a TAK1 independent manner with the involvement of the examined microRNAs.
Keywords: Autophagy; Cisplatin; Pentoxifylline; TAK1; miRNA-26b; miRNA-34a; miRNA-let-7b.
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