VHL-recruiting PROTAC attenuates AKI-CKD transition via simultaneous degradation of Smad3 and stabilization of HIF-2α.

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.