Effect of endoplasmic reticulum stress-mediated excessive autophagy on apoptosis and formation of kidney stones

Aims: This study was designed to reveal the role and underlying mechanism of excessive autophagy mediated by ERS via the PERK-eIF2 alpha pathway in the apoptosis and formation of CaOx kidney stones. Main methods: Ethylene glycol (EG) was used to establish a rat model of CaOx kidney stones, and 100 mg/kg of ERS inhibitor 4-phenylbutyric acid (4-PBA) or 60 mg/kg of autophagy inhibitor chloroquine (CQ) was administered daily to the rats. Four weeks after administration, we collected blood and kidney tissues to analyze the occurrence of ERS and autophagy, apoptosis, renal function, renal tubular crystal deposition, and kidney damage, respectively. Key findings: We observed that both 4-PBA and CQ treatment significantly inhibited the excessive autophagy and reduced apoptosis as well as decreasing p-PERK and p-eIF2 alpha expressions. Meanwhile, the proportion of kidney weight, contents of creatinine and blood urea nitrogen, excretion of neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, and renal tubular deposition were markedly down-regulated. Significance: The findings in this study suggested that ERS induced excessive autophagy via the PERK-eIF2 alpha pathway, regulating cell damage and apoptosis. ERS-mediated inhibition of excessive autophagy effectively protected kidney function and prevented the apoptosis and formation of kidney stones.