Berberine ameliorates contrast‐induced acute kidney injury by regulating HDAC4‐FoxO3a axis‐induced autophagy: In vivo and in vitro

Abstract

AbstractIn hospitals, contrast‐induced acute kidney injury (CI‐AKI) is a major cause of renal failure. This study evaluates berberine's (BBR) renal protection and its potential HDAC4 mechanism. CI‐AKI in rats was induced with 10 mL kg−1 ioversol. Rats were divided into five groups: Ctrl, BBR, CI‐AKI, CI‐AKI + BBR, and CI‐AKI + Tasq. The renal function of CI‐AKI rats was determined by measuring serum creatinine and blood urea nitrogen. Histopathological changes and apoptosis of renal tubular epithelial cells were observed by HE and terminal deoxynucleotidyl transferase (TdTase)‐mediated dUTP‐biotin nick end labeling (TUNEL) staining. Transmission electron microscopy was used to observe autophagic structures. In vitro, a CI‐AKI cell model was created with ioversol‐treated HK‐2 cells. Treatments included BBR, Rapa, HCQ, and Tasq. Analyses focused on proteins and genes associated with kidney injury, apoptosis, autophagy, and the HDAC4‐FoxO3a axis. BBR showed significant protective effects against CI‐AKI both in vivo and in vitro. It inhibited apoptosis by increasing Bcl‐2 protein levels and decreasing Bax levels. BBR also activated autophagy, as indicated by changes in autophagy‐related proteins and autophagic flux. The study further revealed that the contrast agent ioversol increased the expression of HDAC4, which led to elevated levels of phosphorylated FoxO3a (p‐FoxO3a) and acetylated FoxO3a (Ac‐FoxO3a). However, BBR inhibited HDAC4 expression, resulting in decreased levels of p‐FoxO3a and Ac‐FoxO3a. This activation of autophagy‐related genes, regulated by the transcription factor FoxO3a, played a role in BBR's protective effects. BBR, a traditional Chinese medicine, shows promise against CI‐AKI. It may counteract CI‐AKI by modulating HDAC4 and FoxO3a, enhancing autophagy, and limiting apoptosis.