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STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation

Lei Liu,Lu Xu,Shaoqing Zhang,Dong Wang,Guoxia Dong,Hanwen Chen,Xinjian Li,Chi Shu,Rong Wang

Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damages in IR-induced ARF. Rats were administrated with STF-083010 and were subjected to induction of ARF using a ligation method. Then the effect of STF-083010 administration on the renal structure and function, oxidative stress, and inflammation in model rats was assessed. Furthermore, the levels of expression of UPR members and downstream effectors regulating apoptosis were detected as well. The results showed that establishment of the ARF model induced ER stress and impaired the renal structure and function. Administration of STF-083010 ameliorated impairments in the structure and function of the kidneys and the effect was associated with the suppressed oxidative stress and inflammation. At the molecular level, STF-083010 inhibited the prolonged UPR by downregulating the expressions of GRP78, p-IRE1, XBP1s, CHOP, and caspase 3, partially explaining the decreased apoptotic rate. The current study evaluated the potential of STF-083010 in treating ER stress-induced symptoms in ARF for the first time, and the findings demonstrated that STF-083010 resulted in effective treatment outcomes of ARF.