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PPAR-δ activation reduces cisplatin-induced apoptosis via inhibiting p53/Bax/caspase-3 pathway without modulating autophagy in murine renal proximal tubular cells

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Abstract

Background

Cisplatin-induced injury of renal proximal tubular cells results basically from increased apoptosis via mitochondrial damage, and is mitigated by appropriate enhancement of autophagy. Peroxisome proliferator-activated receptor-delta (PPAR-δ) reportedly protects against not only mitochondrial damages but also enhances autophagy. Thus, PPAR-δ may protect against cisplatin-induced kidney injury.

Methods

We examined the protective effects of PPAR-δ activation on cisplatin-induced cellular injury and their detailed mechanisms in a murine renal proximal tubular (mProx) cell line using GW0742, an authentic PPAR-δ activator. Cisplatin-induced cell damages were evaluated by TUNEL assay and immunoblot analyses for p53, 14-3-3, Bax, Bcl2, cytochrome C, and activated caspases. Autophagy status was examined by immunoblot analyses for p62 and LC3.

Results

GW0742 suppressed cisplatin-induced apoptosis of mProx cells by reducing the activation of caspase-3 via attenuating the phosphorylation of p53 and 14-3-3, mitochondrial Bax accumulation, cytochrome C release from mitochondria to the cytosol and ensuing cytosolic caspase-9 activation. In contrast, GW0742 did not diminish cisplatin-enhanced activation of caspases-8 or -12 as extrinsic or endothelium reticulum apoptotic pathways, respectively. The inhibitory effect of GW0742 on cisplatin-induced caspase-3 activation was significantly diminished by silencing of the PPAR-δ gene expression. GW0742 itself had no influence on starvation-stimulated or cisplatin-induced autophagy in mProx cells, suggesting that the protective effects were not mediated by autophagy modification.

Conclusion

Our results indicate that GW0742 may serve as a candidate agent to mitigate cisplatin nephrotoxicity via inhibiting the mitochondrial apoptotic pathway considerably depending on PPAR-δ, without modulating autophagy.

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Acknowledgements

This study was supported by Grants-in-Aid of the Japan Society of Promotion of Science (JSPS KAKENHI Grant Numbers: JP15K09252 to H.K., JP15H04836 to M.I.).

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Authors and Affiliations

  1. Division of Nephrology, Shaoxing Peoples’ Hospital, Shaoxing, China

    Juanping Shan

  2. Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, Fukui, 910-1193, Japan

    Hideki Kimura, Toru Imamoto & Izumi Takeda

  3. Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

    Seiji Yokoi, Kazuko Kamiyama, Mamiko Kobayashi, Daisuke Mikami, Naoki Takahashi, Kenji Kasuno & Masayuki Iwano

  4. Cimic Corporation, Tokyo, Japan

    Takeshi Sugaya

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  1. Juanping Shan
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Correspondence to Hideki Kimura.

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Shan, J., Kimura, H., Yokoi, S. et al. PPAR-δ activation reduces cisplatin-induced apoptosis via inhibiting p53/Bax/caspase-3 pathway without modulating autophagy in murine renal proximal tubular cells. Clin Exp Nephrol 25, 598–607 (2021). https://doi.org/10.1007/s10157-021-02039-2

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