Objectives: Previous studies have shown that hyperuricemia may induce hypertension via subtle renal injury. In hypertensive animal models, hypertension and kidney injury were relieved by endoplasmic reticulum (ER) stress inhibition. This study was undertaken to investigate the role of ER stress in hyperuricemia-induced hypertension and kidney injury. Methods: In animal experiment 1, Sprague-Dawley rats were randomly divided into four groups for 28d: normal controls (NC), hyperuricemia controls (HC, induced by adding 2% oxonic acid and 3% uric acid to food), allopurinol-treated rats (HA), and benzbromarone-treated rats (HB). Animal experiment 2 also comprised four groups for 14d: NC, HC, 4-phenylbutyric acid-treated rats (HP), and tauroursodeoxycholic acid-treated rats (HT). Systolic blood pressures (SBPs) were followed during the experiments, and ER stress markers and histopathology were examined from kidneys obtained at the end of each animal experiment. Results: In animal experiment 1, HC rats had an increase in plasma uric acid and SBP and these are significantly lowered in HA and HB. Glucose-Regulated Protein 78 (GRP78) expression increased in HC and attenuated in HA and HB. In animal experiment 2, HC rats also had an increased in plasma uric acid and SBP and these are significantly reduced in HP and HT. GRP78 expression increased in HC and attenuated in HP and HT. The expression of protein disulfide isomerase (PDI) also increased in HC and attenuated in HP and HT. Renal histopathology revealed that glomerular injury score was higher in HC than NC and reversed in HP and HT. Tubulointerstitial injury was also higher in HC than NC and reversed in HP and HT. Conclusions: In rats, hypertension and kidney injury were induced by hyperuricemia. They were associated with ER stress and improved by either uric acid lowering or ER stress inhibition. In conclusion, hyperuricemia induces hypertension and kidney injury via ER stress.