FXR激动剂CDCA通过KLF11-JAK2/STAT3通路减轻造影剂诱导急性肾损伤

Abstract

Background Contrast-induced acute kidney injury (CI-AKI) represents a major clinical complication in cardiovascular interventions with limited preventive options. This study investigated whether the FXR agonist CDCA protects against CI-AKI via transcriptional upregulation of Krüppel-like factor 11 (KLF11) and subsequent inhibition of the JAK2/STAT3 pathway. Methods and results This study established an iohexol-induced acute kidney injury model in mice and found that the FXR agonist CDCA significantly improved renal function, attenuated renal tissue damage, apoptosis, and inflammatory responses. RNA sequencing revealed that CDCA markedly upregulated the expression of KLF11. Mechanistically, luciferase reporter assays and ChIP experiments confirmed that FXR directly binds to the FXRE sequence in the KLF11 promoter, promoting its transcription. In HK-2 cells, CDCA suppressed the JAK2/STAT3 pathway via the FXR–KLF11 axis, thereby reducing inflammation and apoptosis; whereas knockdown of KLF11 or genetic deletion of FXR abolished the protective effects of CDCA, demonstrating the essential role of the FXR-KLF11 axis in renal protection. Conclusions This study reveals that the FXR agonist CDCA confers renoprotection in CI-AKI by transcriptionally upregulating KLF11 to suppress the JAK2/STAT3 pathway. The identification of the FXR-KLF11 axis advances our understanding of CI-AKI pathogenesis and supports the clinical development of FXR agonists like CDCA as prophylactic therapeutics.