Lead (Pb), a highly poisonous heavy metal and an important occupational hazard, is currently a widespread environmental pollutant. The kidney is especially susceptible to the toxic effects of Pb because of its major role in Pb excretion. Heme oxygenase-1 (HO-1) is an inducible antioxidant enzyme that can mitigate cellular injury. However, its role in Pb-elicited nephrotoxicity remains uncertain. This study was designed to examine the role of HO-1 in lead acetate (PbAc)-induced renal tubular cell injury in vitro. PbAc injury was found to suppress HO-1 expression and impair cell viability, with concomitant depletion of the autophagy proteins LC3-II and Beclin 1. Overexpression of HO-1 dramatically restored autophagy and protected cells against PbAc-induced apoptosis. In addition, pretreatment with 3-methyladenine, an inhibitor of autophagy, aggravated apoptosis and abolished renoprotection by HO-1, suggesting that the anti-apoptotic effect of HO-1 in Pb-induced nephrotoxicity is dependent on enhanced autophagy. Furthermore, HO-1 overexpression abrogated the inhibitory effect of PbAc on the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTORC1) signaling pathway. Pretreatment with an AMPK agonist, 5-aminoimidazole-4-carboxamide-1-β-D ribofuranoside, markedly enhanced autophagic activity and diminished apoptosis. Conversely, inhibition of AMPK phosphorylation abolished the pro-autophagic and anti-apoptotic effects of HO-1 in PbAc-injured cells. Our findings suggest that HO-1 alleviates Pb-induced nephrotoxicity via enhanced autophagy, which involves activation of the AMPK/mTORC1 signaling pathway.
Keywords: AMPK; Heme oxygenase-1; autophagy; lead acetate; mTORC1; nephrotoxicity.
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