4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition

Objective: Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate in vivo models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.

Methods: We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.

Results: Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with in vivo results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT in vitro, supporting ER stress involvement in these processes.

Conclusions: Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.