Abstract
Acute kidney injury (AKI) impairs renal function in the short term and may eventually progress to chronic kidney disease (CKD) in the long term. The activation of Smad3 and an imbalance in hypoxia-inducible factors-α (HIF-α) expression constitute vital mechanisms leading to the AKI-CKD transition. We have designed a Smad3-targeted Proteolysis-Targeting Chimera (PROTAC) named P1705434, which recruited VHL to degrade Smad3 and meanwhile stable HIF-2α levels. We established a cisplatin nephrotoxicity model and folic acid nephropathy (FAN) model to explore its role and possible mechanisms in the early stage and development of AKI. The results demonstrated that P1705434 alleviated inflammation and fibrosis in progressing AKI by degrading Smad3 and increasing HIF-2α. This was confirmed in both the cisplatin nephrotoxicity and FAN mice models, as evidenced by the reduction percentage of maladaptive proximal tubular cells (PT) and down-regulation of the TNF pathway, which ameliorated injury in S3-PT. Furthermore, we identified a transitional collecting duct (tCD) cell type that had a trend to differentiate into fibroblast but P1705434 treatment reduces the propensity of tCD cells and mitochondrial injury in CD cells by up-regulating the oxidative phosphorylation (OXPHOS) pathway.
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Data availability
The scRNA-seq data have been deposited in the CNCB database under the accession ID PRJCA029666 (https://ngdc.cncb.ac.cn/).
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Acknowledgements
This work was supported by the Natural Science Foundation of Guangdong Province, China (2023A1515010539), National Natural Science Foundation of China (82300842), National Natural Science Foundation of China (82170737, 82370707), NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University), Guangzhou Science and Technology Project (202206080010), Guangdong Provincial Key Laboratory of Nephrology, Guangdong International Science and Technology Cooperation Institute of Immune Kidney Disease and Precision Medicine, Guangdong Basic and Applied Basic Research Foundation (2023B0303000013), and 2024 Guangzhou Science and Technology Fund for Agriculture and Social Development Special Topic (2024B03J1337).
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XW, WC, and ST designed all the experiments and supervised the study. YR, DW, and YX conducted the experiments and data collection. YR analyzed data, performed bioinformatics, and drafted the manuscript. JY, YC, JF provided technical support and critical reading of the manuscript. All authors read and approved the final manuscript.
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Ruan, Y., Wang, D., Xu, Y. et al. VHL-recruiting PROTAC attenuates AKI-CKD transition via simultaneous degradation of Smad3 and stabilization of HIF-2α. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08726-w
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DOI: https://doi.org/10.1038/s41419-026-08726-w
