The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway

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Abstract

The thiazolidinedione pioglitazone, which is also a PPAR-γ agonist, now is widely used in patients with hypercholesterolemia and hypertriglyceridemia. NF-κB is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of the present study was to evaluate whether the activation of PPAR-γ attenuates the cisplatin-induced NF-κB activation in cisplatin nephrotoxicity. The results showed that the PPAR-γ agonist pioglitazone decreased the expression of NF-κB p65 transcription target genes (e.g., IL-6, IL-1β, and TNF-α) and inhibited histological injury and inflammatory cells infiltration in cisplatin nephrotoxicity. The suppression of NF-κB activity following pioglitazone treatment inhibited the cisplatin-induced IκB-α degredation and NF-κB p65 subunit translocation. Translocation of the NF-κB p65 subunit depends on p65 acetylation, which primarily regulated by SIRT1 or p300. Notably, AMP kinase (AMPK) activation not only decreased the phosphorylation, activation and p65 interaction of p300 but also increased SIRT1 expression, activation and p65 binding, thus leading to a significant reduction in p65 acetylation. Interestingly, the reduction of IL-6, TNF-α and IL-1β, the inhibition of histological injury and the inflammatory cells infiltration following pioglitazone treatment in cisplatin nephrotoxicity were attenuated after treatment with the PPAR-γ antagonist GW9662. These results suggest that the PPAR-γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through a reduction in p65 acetylation via the AMPK-SIRT1/p300 pathway.

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Zhang, J., Zhang, Y., Xiao, F., Liu, Y., Wang, J., Gao, H., … Xu, G. (2016). The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway. Biochemical Pharmacology, 101, 100–111. https://doi.org/10.1016/j.bcp.2015.11.027

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