DNAJC6 in acute kidney injury: A novel target for protecting renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis.

BACKGROUND

Acute kidney injury (AKI) is a severe clinical syndrome that critically threatens patients' lives and health. It is characterized by complex pathogenesis and lacks effective therapeutic strategies. Mitochondrial homeostasis disruption plays a pivotal role in AKI progression, yet its precise molecular mechanisms remain unclear. This study aimed to investigate the role of DNAJC6 in AKI and its molecular mechanism of mitochondrial homeostasis regulation.

METHODS

Utilizing cisplatin-induced mouse AKI models and human proximal tubular epithelial cell line HK-2, we employed multiple experimental approaches including bioinformatics analysis, cell transfection, immunohistochemical staining, immunofluorescence, TUNEL assay, and mitochondrial function detection to explore the role and molecular mechanisms of DNAJC6 in AKI.

RESULTS

In cisplatin-induced AKI models, renal DNAJC6 expression decreased. DNAJC6 overexpression markedly alleviated kidney injury, reduced cell apoptosis, and attenuated inflammatory responses. Mechanistic investigations revealed that DNAJC6 regulated mitochondrial homeostasis by promoting PGC-1α nuclear translocation. Specifically, DNAJC6 improved mitochondrial respiratory function and reduced mitochondrial oxidative stress levels. Moreover, DNAJC6 enhanced mitochondrial biogenesis and suppressed inflammatory factor expression. Upon PGC-1α knockdown, DNAJC6's protective effects were almost completely abolished, confirming that PGC-1α was a critical molecular mediator.

CONCLUSION

This study elucidated the molecular mechanism by which DNAJC6 protected renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis in AKI. These findings not only provide a novel perspective on AKI pathogenesis but also offer a crucial theoretical foundation for developing potential therapeutic strategies. DNAJC6 emerges as a promising molecular target for AKI treatment.