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

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 NaAsO₂-induced kidney injury in vivo and in vitro. In our study, NaAsO₂ exposure obviously induced renal tubule injury and mitochondrial dysfunction. Meanwhile, NaAsO₂ 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 NaAsO₂-induced nephrotoxicity depended on the activation of Mitophagy. Moreover, the activation of SIRT1 by resveratrol alleviated NaAsO₂-induced acute kidney injury via the activation of Mitophagy in vivo and in vitro. Interestingly, the inhibition of Mitophagy by cyclosporin A (CsA) further exacerbated NaAsO₂-induced nephrotoxicity and inflammation in HK-2 cells. Taken together, our study found that SIRT1-regulated PINK1-/Parkin-dependent Mitophagy was implicated in NaAsO₂-induced acute kidney injury. In addition, we confirmed that PINK1-/Parkin-dependent Mitophagy played a protective role against NaAsO₂-induced acute kidney injury. Therefore, activation of SIRT1 and Mitophagy may represent a novel therapeutic target for the prevention and treatment of NaAsO₂-induced acute renal injury.

PINK1; SIRT1; acute kidney injury; arsenic; mitophagy.