Hydrocortisone alleviates sepsis-induced acute kidney injury through HSF-1-mediated transcriptional suppression of XPO1

Hydrocortisone (HYD) has been suggested as a drug for anti-sepsis treatment, but its clinical efficacy remains controversial. This study aims to evaluate the function of HYD in sepsis-induced acute kidney injury (AKI) and the molecules involved.A mouse model of sepsis was induced by cecal ligation and puncture (CLP) and treated with HYD. The kidney injury biomarkers and inflammatory cytokines in serum samples were determined. The pathological changes in mouse kidney tissues were examined by histological staining. Differentially expressed genes after HYD treatment were screened by microarray analysis. Expression of heat shock transcription factor 1 (HSF1) in the serum samples of septic patients and mouse kidney tissues after HYD treatment was determined. The downstream targets of HSF1 were bioinformatically predicted. Gain- and loss-of-function assays of HSF1 and exportin 1 (XPO1) were performed to validate their functions in AKI.CLP increased the levels of blood urea nitrogen and serum creatinine and the serum levels of pro-inflammatory cytokines. The levels of these biomarkers and the pathological changes and symptoms in mice induced by CLP were significantly alleviated by HYD treatment. HYD elevated the expression of HSF1, which was initially suppressed by CLP in mice. HSF1 bound to XPO1 promoter to suppress its transcription. Downregulation of HSF1 blocked the protective effects of HYD, but further suppression of XPO1 restored the function of HYD and ameliorated the kidney injury in mice.This study demonstrates that HYD alleviates sepsis-induced acute kidney injury through HSF1-mediated transcriptional suppression of XPO1.