Endoplasmic reticulum stress-mediated epithelial-mesenchymal transition contributes to cardiac biomarker-induced...

Renal dysfunction is a frequent comorbidity in heart failure (HF) patients, independently linked to poor prognosis. However, the intricate pathogenesis of the complex interaction between the heart and kidney remains unclear. This study analyzed clinical data from patients with HF and kidney disease. We focused on serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH), which are classic cardiac biomarkers. Results showed that their levels were positively correlated with the severity of renal function impairment. To elucidate HF-induced kidney injury, tandem mass tag (TMT)-labeled quantitative proteomics analysis was employed to identify the variations in protein levels in human kidney tubular epithelial (HK-2) cells that were cultured with either normal human (NH) serum or serum from HF patients. The results highlighted the significant enrichment of endoplasmic reticulum (ER) and ECM-related processes in cardiorenal interactions. Based on these findings, we established in vivo and in vitro models using CK and LDH to simulate the pathogenesis of renal damage caused by heart failure. Mechanistically, we identified TLR4 and CD36 as specific membrane receptors mediating the internalization of CK and LDH, respectively, which subsequently triggered ER stress-induced epithelial-mesenchymal transition (EMT). It was found that EMT and ER stress occurred under CK and LDH combination treatment, along with the activation of Src kinase. Conversely, treatment with an ER stress inhibitor (4-PBA) significantly attenuated CK + LDH-induced EMT and renal injury. Collectively, our findings highlight a novel pathogenic role for cardiac biomarkers and demonstrate that ER stress-mediated EMT is a critical driver of HF-induced renal injury.