Nitrosporeusine A (NA) has been recently reported to exert anti-inflammatory and renal protective effects, but whether NA can attenuate sepsis-associated acute kidney injury (AKI) has not yet been reported. In this study, our results found that cecal ligation and puncture (CLP) reduced renal PGC-1 alpha expression and induced oxidative stress in C57BL/6 mice. PGC-1 alpha overexpression attenuated CLP-induced AKI with decreased oxidative stress, whereas worsened AKI with excessive reactive oxygen species (ROS) production was observed in renal specific PGC-1 alpha knockout (NiPKO) mice. In addition, PGC-1 alpha expression is retained in IL-6(-/-) mice and wild-type (WT) C57BL/6 mice received JAK2/STAT3 inhibition. Finally, administration of NA attenuated CLP-induced AKI with decreased IL-6/sIL-6R axis activation, increased PGC-1 alpha expression, and diminished ROS production in injured kidneys. However, NA failed to attenuate CLP-induced AKI in NiPKO mice. Together, these results suggested that NA attenuates sepsis-associated AKI through the downregulation of IL-6/sIL-6R axis activation-mediated renal PGC-1 alpha suppression. (C) 2019 Elsevier Inc. All rights reserved.