Arsenic Exposure-Induced Acute Kidney Injury by Regulating SIRT1/PINK1/Mitophagy Axis in Mice and in HK-2 Cells

Abstract

Groundwater resources are often contaminated by arsenic, which poses a serious threat to human and animal's health. Some studies have demonstrated that acute arsenic exposure could induce kidney injury because the kidney is a key target organ for toxicity, but the exact mechanism remains unclear. Hence, we investigated the effect of SIRT1-/PINK1-mediated mitophagy on NaAsO 2 -induced kidney injury in vivo and in vitro. In our study, NaAsO 2 exposure obviously induced renal tubule injury and mitochondrial dysfunction. Meanwhile, NaAsO 2 exposure could inhibit the mRNA/protein level of SIRT1 and activate the mitophagy-related mRNA/protein levels in the kidney of mice. In HK-2 cells, we also confirmed that NaAsO 2 -induced nephrotoxicity depended on the activation of mitophagy. Moreover, the activation of SIRT1 by resveratrol alleviated NaAsO 2induced acute kidney injury via the activation of mitophagy in vivo and in vitro. Interestingly, the inhibition of mitophagy by cyclosporin A (CsA) further exacerbated NaAsO 2 -induced nephrotoxicity and inflammation in HK-2 cells. Taken together, our study found that SIRT1-regulated PINK1-/Parkin-dependent mitophagy was implicated in NaAsO 2 -induced acute kidney injury. In addition, we confirmed that PINK1-/Parkin-dependent mitophagy played a protective role against NaAsO 2 -induced acute kidney injury. Therefore, activation of SIRT1 and mitophagy may represent a novel therapeutic target for the prevention and treatment of NaAsO 2 -induced acute renal injury.