Puerarin reverses cadmium-induced lysosomal dysfunction in primary rat proximal tubular cells via inhibiting Nrf2 pathway

Published on Apr 1, 2019in Biochemical Pharmacology4.96
· DOI :10.1016/J.BCP.2018.10.016
Li-Yuan Wang1
Estimated H-index: 1
(SDAU: Shandong Agricultural University),
Rui-Feng Fan5
Estimated H-index: 5
(SDAU: Shandong Agricultural University)
+ 2 AuthorsLin Wang17
Estimated H-index: 17
(SDAU: Shandong Agricultural University)
Abstract Previous studies have shown that oxidative stress-induced inhibition of autophagy plays a pivotal role in cadmium (Cd)-mediated cytotoxicity in primary rat proximal tubular (rPT) cells. The objective of this study is to explore the protective effect of puerarin (PU), a potent antioxidant, on Cd-induced autophagy inhibition and oxidative stress in rPT cells. First, Cd-induced blockage of autophagic flux in rPT cells was obviously restored by PU treatment, evidenced by immunoblot analysis of autophagy marker proteins and tandem fluorescent-tagged LC3 method. Resultantly, Cd-induced autophagosome accumulation was significantly alleviated by PU treatment. Also, Cd-induced lysosomal alkalinization and impairment of lysosomal degradation capacity were obviously recovered by PU, demonstrating that PU can restore Cd-induced lysosomal dysfunction. Moreover, Cd-induced lysosomal membrane permeabilization (LMP) was effectively blocked by PU. Cd-stimulated Nrf2 nuclear translocation and subsequent elevated expression of Nrf2-downstream targets were significantly inhibited by PU treatment. Simultaneously, Cd-elevated protein levels of antioxidant enzymes and glutathione synthesis-related proteins in rPT cells were markedly downregulated by PU treatment. In conclusion, these observations indicate that PU alleviates Cd-induced cytotoxicity in rPT cells through restoring autophagy, blocking LMP and inhibiting Nrf2 pathway, which is intimately related with its antioxidant activity.
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