Apoptosis of Human Kidney Epithelial Cells Induced by High Oxalate and Calcium Oxalate Monohydrate Is Apurinic/Apyrimidinic Endonuclease 1 Pathway Dependent and Contributes to Kidney Stone Formation

Kidney stone formation is a very complex process. Multiple molecules and proteins are involved in its formation. High level of oxalate and calcium oxalate monohydrate (COM, 200 mg/ml) crystals are key elements for this process, but the exact mechanism needs to be defined. HOA has been shown to cause renal cell injury through oxidative stress, leading to potential crystal deposition in the kidneys, which induced apoptosis of kidney epithelial cells. Recent reports indicated that apurinic/apyrimidinic endonuclease 1 (APE1) is involved in DNA repair and redox regulation of transcriptional factors, and APE1-dependent apoptosis is observed in various nephropathy models. Therefore, we investigated the changes of APE1 protein expression in the human kidney epithelial cell line (HK-2) by exposing them to high oxalate and COM in various conditions. The results showed that HOA triggers intracellular reactive oxygen species (ROS) and apoptosis of ILK2 cells. This process was mediated by the abnormal expression, modification, and redistribution of APE1 protein in HK-2 cells. The antioxidant N-acetylcysteine reversed this effect. Our results demonstrated a novel molecular mechanism related to renal epithelial cell injury and kidney stone formation.