TY - JOUR
AU1 - Shan, Juanping
AU2 - Kimura, Hideki
AU3 - Yokoi, Seiji
AU4 - Kamiyama, Kazuko
AU5 - Imamoto, Toru
AU6 - Takeda, Izumi
AU7 - Kobayashi, Mamiko
AU8 - Mikami, Daisuke
AU9 - Takahashi, Naoki
AU1 - Kasuno, Kenji
AU1 - Sugaya, Takeshi
AU1 - Iwano, Masayuki
AB - BackgroundCisplatin-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.MethodsWe 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.ResultsGW0742 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.ConclusionOur 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.
TI - PPAR-δ activation reduces cisplatin-induced apoptosis via inhibiting p53/Bax/caspase-3 pathway without modulating autophagy in murine renal proximal tubular cells
JF - Clinical and Experimental Nephrology
DO - 10.1007/s10157-021-02039-2
DA - 2021-03-01
UR - https://www.deepdyve.com/lp/springer-journals/ppar-activation-reduces-cisplatin-induced-apoptosis-via-inhibiting-p53-2JrLmJTSf5
SP - 598
EP - 607
VL - 25
IS - 6
DP - DeepDyve
ER -