Estudio temporal de proteómica y fosfoproteómica para descifrar la dinámica molecular de la enfermedad renal aguda a...

Acute kidney injury (AKI), characterized by a rapid decline in renal function, has high mortality rates and frequently progresses to chronic kidney disease (CKD). A major contributor to AKI is ischemia-reperfusion injury (IRI). However, the global molecular changes underlying the AKI-to-CKD transition post-IRI remain to be fully elucidated. Using 4D label-free proteomic and phosphoproteomic analyses in a murine unilateral IRI model at 1 hour, 1 day, 3 days, 7 days, and 28 days post-injury, we systematically identified dysregulated proteins, phosphoproteins, and signaling pathways involved in the progression from AKI to CKD. Critically, these analyses consistently revealed the enrichment and sustained activation of NF-κB signaling, a key pathway driving inflammatory and fibrotic responses, across multiple time points. In addition, we identified significant impairment of fatty acid β-oxidation (FAO). Notably, our omics analysis specifically identified the dedicator of cytokinesis (Dock) protein family, with Dock2 emerging as a prime candidate due to its known immune regulatory functions. Dock2 expression showed significant upregulation post-IRI and was found predominantly localized to injured tubular epithelial cells (TECs). Functional validation demonstrated that Dock2 knockdown attenuated pro-inflammatory responses in TECs by inhibiting IKKβ-mediated NF-κB activation in vitro. Consistently, pharmacological inhibition of Dock2 by CPYPP ameliorated renal tubular injury, inflammation, and fibrosis in vivo. To our knowledge, this is the first study to reveal the role and mechanism of Dock2 in the AKI-to-CKD progression post-IRI. In conclusion, our findings delineate molecular mechanisms underpinning the transition from AKI to CKD and nominate Dock2 as a promising therapeutic target for mitigating this process.